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Introduction: F-18-FDG PET/CT has high positive predictive value for the detection of avid lymph node metastases in breast cancer patients. We analysed the effect of upstaging lymph nodes by PET/CT on short-term outcome in stage II/III breast cancer patients. Patients and methods: A total of 278 stage II/III primary breast cancer patients (mean age 48.9 years, range 19-75 years) were re-staged with 18F-FDG PET/CT before start of pre-operative systemic treatment (PST). Patients were divided in three groups based on risk for local recurrence: a low - (T2N0), intermediate - (T0-2N1 and T3NO) and a high-risk group (T0-3N2-3, T3N1 and T4). Within these groups we looked at local recurrence-free survival (LRFS), recurrence-free survival (RFS) and overall survival (OS) within the first 3 years of followup. Results: With a median follow-up (FU) of 50 months the RFS, LRFS and OS were 87%, 88% and 92% respectively for the whole group. PET/CT upstaged 43 patients from the low- and intermediate risk group to the high-risk group, based on detection of >= 4 avid axillary nodes or occult N2/3-disease. Patients upstaged with PET/CT had more events for all three analyses compared to the original risk groups, which resulted in a significantly worse RFS (69.8%; p = 0.03) a nearly significantly worse LRFS (p = 0.052) and no effect in OS (p = 0.433). Discussion: Additional PET/CT staging allows breast cancer patients to be treated according to the true stage, still stage II/III breast cancer patients upstaged to N2/3 by PET/CT have worse short-term outcome, despite adjustment of treatment, than patients staged high-risk with conventional imaging. (C) 2016 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved

Breast cancer guidelines advise sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) on core biopsy at high risk of invasive cancer or in case of mastectomy. This study investigates the incidence of SLNB and SLN metastases and the relevance of indications in guidelines and literature to perform SLNB in order to validate whether SLNB is justified in patients with DCIS on core biopsy in current era. Clinically node negative patients diagnosed from 2004 to 2013 with only DCIS on core needle biopsy were selected from a national database. Incidence of SLN biopsy and metastases was calculated. With Fisher exact tests correlation between SLNB indications and actual presence of SLN metastases was studied. Further, underestimation rate for invasive cancer and correlation with SLN metastases was analysed. 910 patients were included. SLNB was performed in 471 patients (51.8 %): 94.5 % had pN0, 3.0 % pN1mi and 2.5 % pN1. Patients undergoing mastectomy had 7 % SLN metastases versus 3.5 % for breast conserving surgery (BCS) (p = 0.107). The only factors correlating to SLN metastases were smaller core needle size (p = 0.01) and invasive cancer (p

Purpose: All Dutch hospitals are obliged to report their 5-year ipsilateral breast tumor recurrence (IBTR) rate after breast cancer surgery. Experts decided that these rates should not exceed 5 %. This study determined the value of IBTR as an indicator to compare quality of care between hospitals. Methods: All patients with breast cancer (pT1–3, any N, M0) who underwent surgery in 1 of 92 Dutch hospitals from 2003 to 2006 were identified in the Netherlands Cancer Registry. Data of recurrence was retrieved from hospital records. Five-year IBTR rates for breast-conserving surgery (BCS) and mastectomy were calculated by using the Kaplan–Meier method. Hospital variation was presented in funnel plots. Multivariate analysis was used to assess hospital characteristics associated with IBTR rates. Results: A total of 40,892 breast cancer patients were included. The overall 5-year IBTR rate was 2.85 % (95 % confidence interval 2.68–3.03) and was significantly lower for BCS than for mastectomy (2.38 vs. 3.45 %, p < 0.001). IBTR rates decreased over time in both groups. Rates varied between 0.77 and 5.70 % between hospitals. When random variation is taken into account, only extremely high IBTR rates can be detected as deviant from the target value of 5 %. Adjusting for tumor and patient characteristics, analyses showed that a higher volume of mastectomies is associated with lower IBTR rates. Conclusions: Our population-based findings show that IBTR rates in the Netherlands are low and have improved over time. The 5-year IBTR rate as an indicator for quality of care of individual hospitals is of limited value.

Intraoperative assessment of sentinel lymph nodes (SLNs) has the advantage of allowing breast cancer patients with tumor-positive SLNs to avoid a second surgery by immediately proceeding to axillary lymph node dissection (ALND). However, there are several reasons why the use of intraoperative assessment should be questioned. Whereas ALND was traditionally advised for all breast cancer patients with tumor-positive lymph nodes for axillary staging and locoregional control, more recent studies have demonstrated safety of omitting ALND in a substantial number of patients. In addition, there are concerns about the accuracy of intraoperative assessment methods including frozen section analysis, touch preparation cytology and one-step nucleic acid amplification. Moreover, intraoperative assessment of SLNs denies patients the opportunity to contribute to their treatment planning. In our opinion, intraoperative assessment of axillary lymph nodes should be reserved for patients who still have a strict indication for ALND. Patients with clinical node negative disease (cN0) and one or two positive SLNs can be safely treated with breast conserving surgery and radiotherapy. There has been more controversy for cN0 patients who are treated with mastectomy since radiotherapy is not routinely administered in these patients. However, there is increasing evidence that ALND may be omitted in patients undergoing mastectomy who have a low tumor-burden in their SLNs. Therefore, we defend the position that in cN0 patients undergoing mastectomy, SLNB should be performed and full pathologic evaluation of the SLN should be awaited. In cN0 patients undergoing neoadjuvant systemic therapy (NST) intraoperative assessment of SLNs can be omitted since ALND will not provide therapeutic benefit. It is being hypothesized that patients with limited axillary disease prior to NST who remain node-positive after NST could be treated safely with axillary radiotherapy instead of ALND. In these patients, omitting intraoperative assessment might be a reasonable option. In patients with extensive nodal disease prior to NST intraoperative assessment of axillary lymph nodes should be performed.

Background The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) was based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. Methods and materials Patients 60 years, T ≤ 3 cm, pN0(sn) (sentinel node procedure before RT), ductal carcinoma, unifocal on mammogram and MRI, undergo preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks); 6 weeks hereafter a wide local excision is performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). Results From May 2010- 2013, 58 patients (pts) were included. For 52 pts follow up information is available up to at least 3 months after treatment; mean age 67.2 years (59-80); mean tumor size 1.4 cm (0.4-3.2); differentiation grade: grade 1 (n = 22), grade 2 (n = 28), unknown n = 8; mainly ER+PR + neu- (n = 50). 34 pts received hormonal therapy, none chemotherapy. Toxicity Acute RT toxicity grade 0 (23) grade 1(8). Postoperative complications were noted in 9/52 pts (17%): 2/52 had direct post-operative bleeding needing re-surgery; 1/52 developed a hematoma two months after surgery, needing re-surgery; 6/52 (11.5%) had a postoperative wound infection and received oral antibiotics. Of these 6; 1 wound abscess needing re-surgery; 1 small fistula closing within ten months. In the first year 9/52 pts developed localized oedema at the RT side fading away within 9 months. 4/53 pts developed hematoma post surgery. Fibrosis and cosmetic outcome Fibrosis score at 1 year (n = 35): grade 0 (9), grade 1 (21), grade 2 (4) grade 3 (1). Cosmetic outcome was scored at 1 year (n = 28): excellent/good (25; 89%), fair (3;11%). At 2 years follow up: 10/11 patients excellent/good and 1/11 patient fair. Fibrosis was noted in a limited volume. One ipsi-lateral breast tumor recurrence was diagnosed after 12 months at skin entry of the biopsy tract. Discussion The short term results of this PAPBI trial are promising in terms of acute treatment-related toxicities, complications and cosmetic outcome. Our complication rate of 17% (11% wound infection, 8% hematoma) is comparable with others*. Excellent or good cosmetic outcome was found in 90%, improving over time. Longer follow-up and increasing patient inclusion are needed to evaluate treatment efficacy, cosmetic results and toxicity on the longer term. *Mukesh et al (Eur J Surg Oncol 2012; 648 pts Cambridge IMRT trial), 18% infection, 8% hematoma. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-05.

Background The treatment of axillary lymph node metastases after neoadjuvant systemic therapy (NST) remains debatable and axillary lymph node dissection (ALND) is still the standard of care. Marking axillary lymph nodes with radioactive iodine seeds (MARI procedure) is accurate in restaging the axilla after NST (false-negative rate 7 per cent). Here, the potential of tailored axillary treatment, determined by combining the results of PET–CT before NST with those of the MARI procedure after NST, was analysed. Methods A cohort of axillary node-positive patients was used to construct a hypothetical treatment algorithm based on a combination of PET–CT and the MARI procedure. In the algorithm, the number of fluorodeoxyglucose (FDG)-avid axillary lymph nodes (1–3 versus 4 or more) before NST and the tumour status of the MARI node (positive versus negative) after NST were used to tailor axillary treatment. All patients in the cohort underwent ALND, allowing estimation of potential overtreatment and undertreatment. Results A total of 93 patients were included in the study. Between one and three FDG-avid axillary lymph nodes were observed in 59 patients, and four or more in 34 patients. The MARI node was tumour-negative in 32 patients and showed residual disease in 61. Treatment according to the constructed algorithm would have resulted in 74 per cent of patients avoiding an ALND, with potential undertreatment in three patients (3 per cent) and overtreatment in 16 (17 per cent). Conclusion Tailored axillary treatment after NST in node-positive patients, by combining PET–CT before NST and the MARI procedure after NST, has the potential for ALND to be avoided in 74 per cent of patients.

The purpose of this study was to study the impact of changes in clinical practice on outcome in patients treated with breast-conserving therapy (BCT) over a period of 28 years. Patients with early invasive breast cancer, who were treated with BCT at the Netherlands Cancer Institute between 1980 and 2008, were studied. Clinical characteristics, treatment and outcome were compared between groups (1980-1987; 1988-1998; 1999-2008). The main endpoint analyzed was ipsilateral breast tumor recurrence (IBTR). 8485 patients with a median follow-up of 9 years (IQR 6-14 years) were analyzed. The cumulative 5- and 10-year IBTR incidences were, respectively, 2 and 5 % for the whole cohort and 4 and 9 % in patients ≤40 years. Young age was a significant risk factor for IBTR in multivariable analysis. IBTR-free interval was better for patients who received a RT boost (HR 0.65) or systemic therapy (HR 0.52). In later years, patients less often received a boost and more often underwent adjuvant systemic treatment. 761 patients (9.0 %) underwent a re-excision; the tumor resection margins were tumor free for 85 %. In later years (1999-2008), 89 % of patients had a tumor-free margin. The margin status of invasive carcinoma did not influence IBTR, DM rate, or OS. Between 1980 and 2008, locoregional control after BCT remained stable with low IBTR rates, even in young patients. These good results were achieved under the policy of accepting close or focally positive margins, indicating this is a safe approach. The results of this study may help in lowering the re-excision rates, which are high in many centers.

Background An important benefit of neoadjuvant chemotherapy is the increased potential for breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not easily assessed, rendering axilla-conserving treatment difficult. The aim was to assess a new surgical method for evaluating the axillary response to chemotherapy. Methods Before neoadjuvant chemotherapy, proven tumour-positive axillary lymph nodes were localized using ultrasound-guided insertion of iodine-125-labelled (I-125) seeds. After neoadjuvant chemotherapy, the marked lymph nodes were removed selectively with the use of a γ probe. A complete axillary lymph node clearance was carried out to determine whether the pathological response in the marked node was indicative of that in the other lymph nodes. Results Tumour-positive axillary lymph nodes were localized successfully with I-125 seeds in 15 patients. The marked lymph node was detected and removed selectively after neoadjuvant chemotherapy in all patients. The pathological response to chemotherapy in the marked lymph node was indicative of the overall response in other removed lymph nodes. Conclusion This study showed that marking and selectively removing metastatic lymph nodes after neoadjuvant chemotherapy was feasible. The tumour response in the marked lymph node may be used to tailor further axillary treatment, making axilla-conserving surgery a possibility.

BACKGROUND: The Netherlands Cancer Institute used DNA microarray analyses to identify a 70-gene expression profile strongly predictive of a short interval to distant metastases in breast cancer. For patients with small tumors, the signature is not yet adequately validated. Furthermore, 95% of estrogen-receptor or triple-negative tumors are assigned to poor prognosis by the profile. METHODS: A pooled database was constructed containing clinical, pathological and microarray data of 1696 patients. The database will be used to study the performance of the 70-gene profile in patients with small-sized T1 tumors. In addition, patients with triple-negative tumors will be identified and whole genome microarray analysis will be performed of these tumors to develop a new prognostic gene expression profile for this subgroup. RESULTS AND CONCLUSIONS: If the 70-gene profile is accurate for small tumors, patients at risk may be assigned to adjuvant treatment. A new prognostic classifier for triple-negative tumors may help to identify women, in whom adjuvant treatment may safely be omitted.

Introduction Locoregional breast cancer recurrence can be detected at an advanced stage of the disease. To achieve local control for these larger local breast cancer recurrences, wide soft tissue resections with autologous tissue coverage of the defect is an option. The aim of this study was to assess the local control and morbidity of surgical salvage of patients with advanced local breast cancer recurrence using autologous tissue closure of the defect. Material and methods Eighty-eight patients were treated with wide soft tissue resections with autologous tissue coverage from 1993 to 2006. Two different operating techniques were used for closure of the defect; transposition of the greater omentum covered with split skin graft and the latissimus dorsi musculo-cutaneous flap. Demographic, treatment and mortality information were retrieved from original patients' files. Results Postoperatively 10 patients (11%) developed complications which required an additional operation. In patients treated with curative intent ( n =67) median disease-free interval after extensive surgery was 24 months and median survival was 45 months. In 42 patients (47% of all included patients) the first recurrence after extensive surgery was a locoregional relapse. The two surgical techniques did not differ in overall survival ( p =0.739) and local control. Conclusion Large soft tissue resection for extensive local relapse of breast cancer may result in lasting local control in half of the patients with acceptable morbidity.

Objectives: The standard treatment for hormone-receptor positive, postmenopausal early breast cancer patients is 5 years of adjuvant endocrine therapy. Previous studies demonstrate that prolonging adjuvant endocrine therapy may improve disease-free survival. However, endocrine therapy is known for its adverse events, which may negatively affect Quality of Life (QoL). The aim of this study is to assess the impact of extended adjuvant endocrine therapy on long-term QoL outcomes. Methods: 471 patients selected from the IDEAL trial were invited to complete a questionnaire 1-1.5 years after starting with extended therapy. The questionnaire consisted of the EORTC QLQ-C30 and QLQ-BR23 questionnaires. Mean QoL outcomes were compared with EORTC reference values for stage I and II breast cancer patients and the general population. Furthermore, QoL outcomes were compared between different treatment regimens. A difference of eight points was considered clinically relevant. Results: IDEAL patients receiving extended adjuvant endocrine therapy have significantly and clinically relevant better global QoL compared with reference values for stage I and II breast cancer patients (79.6 versus 64.6; p

In the MRISC study, women with an inherited risk for breast cancer were screened by a 6-month clinical breast examination (CBE) and yearly MRI and mammography. We found that the MRISC screening scheme could facilitate early breast cancer diagnosis and that MRI was a more sensitive screening method than mammography, but less specific. In the current study we investigated the contribution of MRI in the early detection of breast cancer in relation to␣tumor characteristics. From November 1999 to October 2003, 1909 women were included and 50 breast cancers were detected, of which 45 were evaluable and included in the current study. We compared the characteristics of tumors detected by MRI-only with those of all other (non-palpable) screen-detected tumors. Further, we compared the sensitivity of mammography and MRI within subgroups according to different tumor characteristics. Twenty-two (49%) of the 45 breast cancers were detected by MRI and not visible at mammography, of which 20 (44%) were also not palpable (MRI-only detected tumors). MRI-only detected tumors were more often node-negative than other screen-detected cancers (94 vs. 59%; P = 0.02) and tended to be more often ≤1 cm (58 vs. 31%; P = 0.11). MRI was more sensitive than mammography for a wide spectrum of invasive tumor characteristics i.e., size, nodal status, histology, grade and ER status. Half of the breast cancers detected in this study were visible by MRI only and these tumors were smaller and significantly more often node-negative than other screen-detected tumors, suggesting that MRI makes an important contribution to the early detection of hereditary breast cancer.

A study was undertaken to describe the treatment preferences and choices of patients with breast cancer, and to identify predictors of undergoing breast-conserving therapy (BCT) or mastectomy (MT). Consecutive patients with stage I/II breast cancer were eligible. Information about predictor variables, including socio-demographics, quality of life, patients' concerns, decision style, decisional conflict and perceived preference of the surgeon was collected at baseline, before decision making and surgery. Patients received standard information (n = 88) or a decision aid (n = 92) as a supplement to support decision making. A total of 180 patients participated in the study. In all, 72% decided to have BCT (n = 123); 28% chose MT (n = 49). Multivariate analysis showed that what patients perceived to be their surgeons' preference and the patients' concerns regarding breast loss and local tumour recurrence were the strongest predictors of treatment preference. Treatment preferences in itself were highly predictive of the treatment decision. The decision aid did riot influence treatment choice. The results of this study demonstrate that patients' concerns and their perceptions of the treatment preferences of the physicians are important factors in patients' decision making. Adequate information and communication are essential to base treatment decisions on realistic concerns, and the treatment preferences of patients, (C) 2004 Cancer Research UK

Selection of patients for randomised clinical trials may have a large impact on the applicability of the study results to the general population presenting the same disorder. However, clinical characteristics and outcome data on non-entered patients are usually not available. The effects of patient selection for the EORTC 10853 trial investigating the role of radiotherapy in breast conserving therapy for ductal carcinoma in situ have been studied, in an analysis of all patients treated for ductal carcinoma in situ in five participating institutes. The reasons for not entering patients were evaluated and treatment results of the randomised patients were compared to those not entered. A total of 910 patients were treated for ductal carcinoma in situ. Of these, 477 (52%) were ineligible, with the size of the lesion being the main reason for ineligibility (30% of all ductal carcinoma in situ). Of the 433 eligible patients, 278 (64%) were randomised into the trial. The main reasons for non-entry of eligible patients were either physicians' preference for one of the treatment arms (26%) or patients' refusal (9%). These percentages showed significant variation among the institutes. At 4 years follow-up, those patients not entered in the trial and treated with local excision and radiotherapy, had higher local recurrence rates than the patients randomised in the trial and treated with the same approach, (17 vs 2%, P=0.03). The patients treated with local excision alone had equal local recurrence rates (11% in both groups). Selection of patients may explain the differences in outcome of the randomised patients, and those not-entered. Thus, the results of this trial may not be applicable to all patients with ductal carcinoma in situ. British Journal of Cancer (2002) 21, 615–620. doi:10.1038/sj.bjc.6600514 www.bjcancer.com © 2002 Cancer Research UK

Aims To evaluate the diagnostic and therapeutic procedures which were followed in a European Organization for Research and Treatment of Cancer (EORTC) randomized clinical trial investigating the role of radiotherapy in breast-conserving treatment (BCT) for ductal carcinoma in situ (DCIS) of the breast. Methods The medical files of 824 of the 1010 randomized patients (82%) were reviewed during site visits to 30 participating institutes. Results Large variations occurred, particularly in the surgical procedures and histopathological work-up which were performed. Important risk factors like tumour size and margin status were poorly quantified in the medical files. Conclusions These findings emphasize the need for establishing uniform guidelines for diagnostic and therapeutic procedures for DCIS, and for clearly defined risk factors for recurrence after BCT for DCIS. Because of its randomized nature, the main question of the trial, i.e. the effect of radiotherapy on the risk of local recurrence, will not be influenced by variation. The risk of local recurrence in itself, and hence the success of BCT for DCIS, may however be influenced by the quality of the initial procedures that were conducted.

Background Following treatment for primary breast cancer, annual mammography and regular clinical breast examination is advised. The aim of this study was to investigate whether annual mammography resulted in an improvement in stage of contralateral breast cancers compared with mammography performed at a longer interval. Methods This was a retrospective analysis of patients treated for breast cancer, who developed a contralateral breast cancer between 1977 and 1998. Patients were stratified into two groups according to mammographic interval. Results Data were available for 275 patients who developed contralateral breast cancer during follow-up. Annual mammography was performed in 51 per cent; these patients were a mean of 5 years younger at diagnosis. Patients who had annual or biennial mammography had comparable rates of impalpable contralateral breast cancer, 30 and 27 per cent respectively. The tumours were of favourable stages in 60 and 58 per cent respectively. Five-year disease-free survival following diagnosis of contralateral breast cancer was 75 per cent in both groups. When the contralateral lesion was detected by mammography, disease-free survival was better, irrespective of the stage of the ipsilateral breast cancer. Conclusion No difference was found between the two groups in stage distribution and disease-free survival after the diagnosis of contralateral breast cancer. Survival was better in patients in whom the contralateral breast cancer was first detected by mammography.

Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction. Electronic supplementary material The online version of this article (doi:10.1007/s10549-014-2954-2) contains supplementary material, which is available to authorized users.

Objectives: The standard treatment for hormone-receptor positive, postmenopausal early breast cancer patients is 5 years of adjuvant endocrine therapy. Previous studies demonstrate that prolonging adjuvant endocrine therapy may improve disease-free survival. However, endocrine therapy is known for its adverse events, which may negatively affect Quality of Life (QoL). The aim of this study is to assess the impact of extended adjuvant endocrine therapy on long-term QoL outcomes. Methods: 471 patients selected from the IDEAL trial were invited to complete a questionnaire 1e1.5 years after starting with extended therapy. The questionnaire consisted of the EORTC QLQ-C30 and QLQ-BR23 questionnaires. Mean QoL outcomes were compared with EORTC reference values for stage I and II breast cancer patients and the general population. Furthermore, QoL outcomes were compared between different treatment regimens. A difference of eight points was considered clinically relevant. Results: IDEAL patients receiving extended adjuvant endocrine therapy have significantly and clinically relevant better global QoL compared with reference values for stage I and II breast cancer patients (79.6 versus 64.6; p < 0.01) and the general population (79.6 versus 71.2; p < 0.01). Similar results were found for emotional function, pain, appetite loss, diarrhea and financial problems. Between treatment regimens prior to extended adjuvant endocrine therapy, differences were only found on specific QoL domains (e.g. arm symptoms). Conclusion: Breast cancer patients on extended adjuvant endocrine therapy have significantly and clinically relevant better global QoL compared with other stage IeII breast cancer patients and the general population, 6e8.5 years after diagnosis.

The aim of this study was to develop a standardised surgical report for breast-conserving procedures, supporting the systematic documentation of the different aspects of the surgery. The surgical procedure for tumourectomy and axillary clearance was translated into a series of steps that could be quantitatively documented. This description was submitted twice to a group of surgeons from different departments to ensure that all steps that are considered to have relevance for outcome were included and that no superfluous data were collected. After two corrective phases, a first test format was developed. Between February 1993 and May 1994, seven surgical departments, participating in EORTC trials, completed this questionnaire for a number of their patients. The data collected related to general information on the department, the tumour excision itself, the axillary dissection and, in a later phase, on pathology. 269 questionnaires (264 tumour excisions, 259 axillary dissections and 189 pathology reports) were collected and analysed. Even though the participating departments were involved in a single trial on breast-conserving surgery and had previously developed regular contacts about the practical aspects of treatment, many differences were detected. In general, variations were found in the waiting time between treatment prescription and execution, experience of the surgeon, duration of the procedure, and the use of prophylactic antibiotics. Also, in the practical execution of the procedure, major variations in the type of incision, width of tumour excision, closure of the breast tissue and skin, the use of frozen sections and the extent of the axillary dissection were found. The most relevant differences and their possible consequences are discussed. It has been proven possible and feasible to document quantitatively a surgical procedure. The fact that within a group of surgeons participating in the same clinical trials, many differences in the surgical techniques are observed, stresses the need to reach a consensus on a stricter set of guidelines for breast-conserving procedures and their documentation, especially when conducting clinical trials.

BACKGROUND: Overexpression of HER-2 is observed in 15–25% of breast cancers, and is associated with increased risk of recurrence. Current guidelines recommend trastuzumab and chemotherapy for most HER-2-positive patients. However, the majority of patients does not recur and might thus be overtreated with adjuvant systemic therapy. We investigated whether the 70-gene MammaPrint signature identifies HER-2-positive patients with favourable outcome. METHODS: In all, 168 T1–3, N0–1, HER-2-positive patients were identified from a pooled database, classified by the 70-gene signature as good or poor prognosis, and correlated with long-term outcome. A total of 89 of these patients did not receive adjuvant chemotherapy. RESULTS: In the group of 89 chemotherapy-naive patients, after a median follow-up of 7.4 years, 35 (39%) distant recurrences and 29 (33%) breast cancer-specific deaths occurred. The 70-gene signature classified 20 (22%) patients as good prognosis, with 10-year distant disease-free survival (DDFS) of 84%, compared with 69 (78%) poor prognosis patients with 10-year DDFS of 55%. The estimated hazard ratios (HRs) were 4.5 (95% confidence interval (CI) 1.1–18.7, P ¼0.04) and 3.8 (95% CI 0.9–15.8, P ¼0.07) for DDFS and breast cancer-specific survival (BCSS), respectively. In multivariate analysis adjusted for known prognostic factors and hormonal therapy, HRs were 5.8 (95% CI 1.3–26.7, P ¼0.03) and 4.7 (95% CI 1.0–21.7, P ¼0.05) for DDFS and BCSS, respectively. INTERPRETATION: The 70-gene prognosis signature is an independent prognostic indicator that identifies a subgroup of HER-2-positive early breast cancer with a favourable long-term outcome.

Purpose The 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530-536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. Methods We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer (N = 123

Background The aim of the study was to assess the risk of invasion and axillary lymph node metastasis in patients with ductal carcinoma in situ (DCIS) diagnosed by preoperative core-needle biopsy. The data were used to select criteria for patients in whom sentinel node (SN) biopsy might be indicated. Methods One hundred and seventy-one women with 172 DCIS lesions diagnosed by core-needle biopsy were analysed. Axillary staging was performed by SN biopsy, axillary node sampling, or level 1–2 axillary lymph node dissection. Results Invasive breast cancer was found in the surgical specimens from 45 tumours (26·2 per cent). Risk factors for invasion were a palpable lesion (odds ratio (OR) 2·95 (95 per cent confidence interval 1·20 to 7·26); P = 0·019), presence of a mass on mammography (OR 3·06 (1·43 to 6·56); P = 0·004), and intermediate (OR 5·81 (1·18 to 28·57); P = 0·030) or poorly differentiated (OR 5·46 (1·17 to 25·64); P = 0·031) tumour grade. Lymph node metastases were found in ten women with DCIS and invasion on final pathology. Factors associated with metastases were age 55 years or less (P = 0·030), invasion of 1·0 cm or more (P < 0·001) and the presence of vascular invasion (P = 0·001). Conclusion SN biopsy should be considered in women with an initial diagnosis of DCIS on core-needle biopsy who are at risk for invasion; this includes women with a palpable lump, a mass on mammography, and intermediate or poor tumour grade.

Aim To compare the breast cancer stages found during MG alone surveillance in women at increased risk with those detected in a program where MRI was added. Methods Stage results of in a retrospective MG alone study of prospectively followed patients, compared with the pooled stage results of breast cancers MG/MRI surveillance. Results One hundred and-fifty-one patients were detected with a first or contralateral breast cancer. Interval cancers were diagnosed in 56% of the BRCA1, 42% of the BRCA2 and 28% of the non-BRCA carriers. A considerable proportion of the breast cancers were detected with breast self-examination alone: 41%, 27% and 31% respectively. Nevertheless the established goals for biennial population screening were reached, except for the BRCA2 carriers, but this group was small. Comparison with pooled data from published MG/MRI surveillance studies did not show significant differences in the stages, except for the BRCA2 carriers. Conclusion Breast cancers detected in a MG alone surveillance program for women at increased risk fulfill most goals set for population screening except for the BRCA2 carriers. Breast self-examination appears to be a valuable additional detection method especially for BRCA1 carriers, who are at risk of developing a highly proliferating breast cancer.

The timing of the sentinel lymph node biopsy (SNB) is controversial in clinically node negative patients receiving neoadjuvant chemotherapy (NAC). We studied variation in the timing of axillary staging in breast cancer patients who received NAC and the subsequent axillary treatment in The Netherlands. Patients diagnosed with clinically node negative primary breast cancer between 1st January 2010 and 30th June 2013 who received NAC and SNB were selected from the Netherlands Cancer Registry. Data on patient and tumour characteristics, axillary staging and treatment were analysed. Two groups were defined: (1) patients with SNB before NAC (N = 980) and (2) patients with SNB after NAC (N = 203). Eighty-three percent of patients underwent SNB before NAC, with large regional variation (35-99%). The SN identification rate differed for SNBs conducted before and after NAC (98% versus 95%; p = 0.032). A lower proportion of patients had a negative SNB when assessed before NAC compared to after (54% versus 67%; p = 0.001). The proportion of patients receiving any axillary treatment was higher for those with SNB before NAC than after (45% versus 33%; p = 0.006). In conclusion, variation exists in the timing of SNB in clinical practice in The Netherlands for clinically node negative breast cancer patients receiving NAC. The post-NAC SN procedure is, despite some lower SN identification rate, associated with a significantly less frequent axillary treatment and thus with less expected morbidity. The effect on recurrence rate is not yet clear. Patients in this registry will be followed prospectively for long-term outcome. (C) 2015 Elsevier Ltd. All rights reserved

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The purpose of this study was to determine which histological factors are associated with an increased risk for local recurrence in the breast after breast-conserving therapy for early breast cancer (TNM stage I and II) and whether risk patterns vary according to menopausal status and type of local recurrence. Through complete follow-up of the patients of eight regional radiation oncology departments, two cancer institutes and one surgical clinic in The Netherlands, 360 patients were identified with local recurrence in the breast after having received breast-conserving therapy (local tumour excision, axillary dissection and irradiation of the whole breast and a boost to the tumour bed) during the 1980s. For each case, two controls with a follow-up of similar duration without local recurrence were randomly selected. Histological slides of the primary tumour were reviewed. Among premenopausal patients the risk of recurrence for those younger than 35 years was significantly higher than that for premenopausal patients of 45 years or older (relative risk (RR) 2.9; 95% confidence interval (95% CI) 1.3-6.6, P < 0.05). The risk of recurrence at or near the site of the primary tumour was most significantly increased for patients with high grade extensive intraductal component (EIC) adjacent to the primary tumour (RR 4.1; 95% CI 1.7-9.8, P < 0.01). Microscopic margin involvement was an important risk indicator for diffuse recurrence and recurrence in the skin of the breast, especially in the presence of vascular invasion (RR 25; 95% CI 4.0-150, P < 0.001). To prevent local recurrence at or near the site of the primary tumour, local excision with a 1-2 cm margin of healthy tissue and a 15 Gy boost seemed adequate local treatment for patients with well differentiated EIC. In contrast, a wider surgical margin, a higher boost dose or mastectomy should be considered for patients with poorly differentiated EIC. Microscopic margin involvement in the presence of vascular invasion significantly increases the risk of diffuse recurrence or recurrence in the skin.

Purpose. In the past 15 years breast conserving therapy (BCT) has become an important treatment option for primary breast cancer. Thirty three angiosarcomas (AS) after BCT have been described in a total of 20 published reports. Limited follow-up data and the lack of information on incidence of AS prompted the authors to review the comprehensive experience in the Netherlands. Methods. Between 1987 and 1995 twenty-one patients with BCT-associated AS were diagnosed in the Netherlands. Follow-up after diagnosis of AS ranged from 6 to 82 months with a median of 24 months. Information on the total number of patients treated with BCT and on the numbers of angiosarcoma in the breast was obtained. Results. The median interval between BCT and AS was 74 months (range: 29–106) and appeared to decrease with higher age. Detection of skin changes followed by incisional biopsy provided the diagnosis. Two year overall (OS) and disease free survivals were 72% (s.e. 10.9) and 35% (s.e. 10.7), respectively. Two year OS after initial complete surgical resection was 86% (s.e. 9.3) compared to 0% after incomplete resection of the AS (P=0.04). The estimated incidence of AS after BCT is 0.16%. Conclusions. BCT-associated AS arises after a relatively short interval. Although the incidence of AS is low, the absolute number of patients at risk is increasing. This calls for vigilance concerning skin changes occurring after BCT. An incisional biopsy provides the only reliable diagnosis. The prognosis appears to be related to the completeness of surgical resection.

The prognosis of patients with stage IIIB breast carcinoma with tumour spread to the apical axillary lymph nodes has hardly improved despite adequate locoregional control and the introduction of systemic adjuvant therapy. A combined modality regimen that includes anthracyclin-based chemotherapy, high-dose chemotherapy with peripheral stem cell support and radiation and hormonal therapy is currently under investigation in this subset of patients. The present study aims to document the efficacy and feasibility of dose-intensive epidoxorubicin in combination with a standard dose of 5-fluorouracil and cyclophosphamide as up-front chemotherapy in this setting. A preoperative chemotherapy regimen consisting of three courses of 5-fluorouracil 500 mg m-2, epidoxorubicin 120 mg m-2 and cyclophosphamide 500 mg m-2 (FE120C) was administered at 21 day intervals without haematopoietic growth factors to 70 patients with apex node-positive disease. All patients were below 60 years of age and had not had prior chemotherapy or radiotherapy. Sixty-six patients were evaluable for clinical response and histopathological examination could be performed in 62 of these. Thirteen patients achieved a clinical complete response (20%). Of these patients, microscopic examination of the mastectomy specimen revealed absence of malignant cells in two and exclusively ductal carcinoma in situ (DCIS) in another two patients. In addition, of the 46 patients (70%) with a clinical partial response, at pathological examination one patient had sclerosis only and four had DCIS. This results in a pathological complete response in three (5%) of all patients and absence of invasive carcinoma in 10%. None of the patients progressed during chemotherapy. The major toxicity was moderate bone marrow suppression with a median white blood count (WBC) nadir of 1800 microliters-1 (range 500-4900). Other toxicities were mild. The full planned dose could be given without delays in 66 of 70 patients FE120C is well tolerated and is highly effective as up-front chemotherapy in relatively young patients with high-risk breast cancer, with a 90% (CI 74-98%) clinical objective response rate.

In 29 chemotherapy-naive patients with stage II-III breast cancer, peripheral blood stem cells (PBSCs) were mobilised following fluorouracil 500 mg m-2, epirubicin 90-120 mg m-2 and cyclophosphamide 500 mg m-2 (FEC) and granulocyte colony-stimulating factor (G-CSF; Filgrastim) 300 microgram s.c. daily. In all but one patient, mobilisation was successful, requiring three or fewer leucocytopheresis sessions in 26 patients; 28 patients subsequently underwent high-dose chemotherapy consisting of carboplatin 1600 mg m-2, thiotepa 480 mg m-2 and cyclophosphamide 6 g m-2 (CTC) followed by PBSC transplantation. Haemopoietic engraftment was rapid with a median time to neutrophils of 500 x 10(6) l(-1) of 9 days (range 8-10) in patients who received G-CSF after PBSC-transplantation; platelet transfusion independence was reached within a median of 10 days (range 7-16). Neutropenic fever occurred in 96% of patients. Gastrointestinal toxicity was substantial but reversible. Renal, neural or ototoxicity was not observed. Complications related to the central venous catheter were encountered in 64% of patients, with major vein thrombosis occurring in 18%. High-dose CTC-chemotherapy with PBSC-transplantation, harvested after mobilisation with FEC and G-CSF, is reasonably well tolerated without life-threatening toxicity and is a suitable high-dose strategy for the adjuvant treatment of breast cancer.

Summary Background The prognosis of patients with stage III B breast carcinoma with metastasis to the apical axillary lymph nodes is poor despite adequate local control achieved by surgery and/or radiation therapy. This study evaluated the feasibility of a dose-intensive up-front chemotherapy regimen in this subgroup of patients. Patients and methods A preoperative chemotherapy regimen consisting of 3 courses of fluorouracil 500 mg/m2, dose-intensive epidoxorubicin 120 mg/m2 and cyclophosphamide 500 mg/m2 (DIE-FEC), was administered at 21-day intervals without hematopoietic growth factors to 31 patients with apex-positive disease. All patients were below 60 years of age and none had had prior chemotherapy or radiotherapy. Results Seven patients achieved clinical complete responses (23%), and 21 achieved clinical partial responses (68%); three patients had stable disease (10%), one of whom had only ductal carcinoma in situ at histopathologic evaluation, which suggested an additional response to therapy. The major toxicity was moderate bone marrow suppression with a median WBC nadir of 1650/u.l (range 500-4600). Other toxic effects were mild. Conclusions DIE-FEC is well-tolerated and highly effective as up-front chemotherapy in relatively young patients with high-risk breast cancer, with a 90% (CI 74%-98%) clinical objective response rate.

Adjuvant! online (AOL) is a web-based tool that calculates individualized 10-year survival probabilities and predicted benefit of adjuvant systemic therapy. The AOL model was constructed using data from breast cancer patients recorded in the US population-based SEER registry and has not yet been validated in any large European series. European patients may differ from those in the US with regard to prognostic factors and intrinsic tumor characteristics. Therefore the aim of our study was to validate AOL in Dutch patients, investigating both its calibration and discriminatory accuracy.Patients who were treated at the Netherlands Cancer Institute for breast cancer between 1987 and 1998 were selected according to the following criteria: pT1-3, pN0-3, M0, definitive primary surgery, and complete axillary staging. Median follow-up was 11.7 years; >96% of patients had more than 10 years follow-up. Clinicopathological characteristics and adjuvant treatment data were entered into the AOL version 8.0 batch processer, with blinding to outcome.For all 5380 patients included, the 10-year observed overall survival (69.0%) and breast cancer-specific survival (78.6%) rates as compared to the 10-year rates predicted by AOL (69.1% and 77.8%, respectively) were within 1% and not statistically different. Moreover, differences between predicted and observed outcomes were within 2% for most relevant clinicopathological subgroups. Subsets of patients for which there was a discrepancy between the predicted outcomes by AOL and the actual observed outcomes included patients under 40 years, for which both the predicted overall and breast cancer-specific survival were overly optimistic (Pred – Obs: by 4.2% and 4.7% respectively; p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4031.

11090 Background: Adjuvant! is a web-based tool that calculates individualized 10-year survival probability and estimates the benefit of adjuvant systemic therapy based on age, co-morbidity, tumor size, tumor grade, number of involved lymph nodes and estrogen-receptor status. The Adjuvant! model was constructed using observed overall survival (OS) for women diagnosed with breast cancer between 1988 and 1992 recorded in the US SEER registry (surveillance, epidemiology and end results) and has not yet been validated in any European series. It is of interest to see whether intrinsic characteristics of tumors and survival of Dutch patients may differ from those in the US. Methods: For this validation all patients who were treated at the Netherlands Cancer Institute for primary breast cancer between 1987 and 1998 were selected according to the following criteria: T1–3 tumor, N0–3, M0, definitive primary surgery, complete axillary staging, and no prior malignancies. Follow-up for OS was complete for >99% of the patients until at least February 2007 (median follow-up 11.7 years). Clinicopathological characteristics as mentioned above and adjuvant treatment data were entered into Adjuvant! version 8.0 for each individual, blinded to the clinical outcome, to calculate predicted 10-year outcomes. Results: In this hospital-based cohort of 5381 patients, all known prognostic factors were significant predictors of overall survival. Across all patients, the 10-year OS was excellently predicted by Adjuvant! (predicted OS - observed OS=0.2%; p=n.s.). Also, for most relevant clinicopathological subgroups the differences between predicted and observed OS were within 2%. Adjuvant underestimated the OS in patients with tubular type of breast cancer (predicted - observed = -6.8; p [Table: see text]