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Background: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane., Patients and Methods: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated., Results: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4., Conclusion: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years.

Purpose: In the adjuvant setting, specific adverse events (AEs) such as vasomotor symptoms (VMS) and musculoskeletal AEs are associated with relapse-free survival in aromatase inhibitor (AI)-treated patients. In the neoadjuvant setting, specific AEs may be associated with tumor response to AIs as well., Methods: Between 2007 and 2012, 107 patients participated in the prospective TEAMIIA trial, a prospective, phase II trial investigating 6 months of neoadjuvant exemestane in patients with strongly ER-positive breast cancer. Radiological response (≥30% decrease in tumor size) was studied in relation to VMSs and MSAEs. Pearson's Chi-Square tests and multivariate logistic regression analyses were used to evaluate of statistical significance (p < 0.05)., Results: Out of 102 patients 26 patients (25.4%) experienced at least one episode of VMS and 27 patients (26.4%) experienced MSAE. Out of 240 reported adverse events, 71 were specific AEs (40 MSAEs, 31 VMSs). Radiological response was greater in patients who reported VMSs compared to patients who did not (70.8% vs. 49.3%, multivariate OR 2.91, 95% C.I. 1.03-8.26, P = 0.045). No significant advantage towards better response was observed in patients who experienced MSAEs (60.0% vs. 53.3%, univariate OR 1.33, 95% C.I. 0.53-3.38, P = 0.545)., Conclusion: VMSs are associated with tumor response to neoadjuvant exemestane and may be useful for predicting treatment outcomes of AI treatment at an early stage in patients treated with neoadjuvant AIs., (Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression.

Background: It is unknown what minimal benefit in disease-free survival older patients with breast cancer require from adjuvant systemic therapy, and if this differs from that required by younger patients. We prospectively examined patients' preferences for adjuvant chemotherapy (aCT) and adjuvant hormonal therapy (aHT), factors related to minimally-required benefit, and patients' self-reported motivations., Patients and Methods: Fifty-two younger (40-64 years) and 29 older (≥ 65 years) women with a first primary, invasive tumor were interviewed post-surgery, prior to receiving aCT/aHT recommendation., Results: The proportions of younger versus older participants who would accept, refuse, or were undecided about therapy were 92% versus 62%, 4% versus 24%, and 4% versus 14% for aCT, and 92% versus 59%, 8% versus 17%, and 0% versus 24% for aHT. The proportion of older participants who would refuse rather than accept aCT was larger than that of younger participants (P = .005). No significant difference was found for aHT (P = .12). Younger and older participants' minimally-required benefit, in terms of additional 10-year disease-free survival, to accept aCT (median, 5% vs. 4%; P = .13) or aHT (median, 10% vs. 8%; P = .15) did not differ. Being single/divorced/widowed (odds ratio [OR], 0.16; P = .005), presence of geriatric condition (inability to perform daily activities, incontinence, severe sensory impairment, depression, polypharmacy, difficulties with walking; OR, 0.27; P = .047), and having a preference to make the treatment decision either alone or after considering the clinician's opinion (active role; OR, 0.15; P = .012) were independently related to requiring larger benefits from aCT. The most frequent motivations for/against therapy included the wish to survive/avoid recurrence, clinician's recommendation, side effects, and treatment duration (only aHT)., Conclusion: Whereas older participants were less willing to accept aCT than younger participants, no significant difference was found for aHT. However, a majority of older participants would still accept both therapies. Adjuvant systemic therapy should be discussed with eligible patients regardless of age., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous retrospective studies have shown that physical functioning in older cancer survivors is affected after treatment, yet prospective data are lacking. The aim of this study was to assess change in physical functioning in different age groups of patients with hormone receptor-positive breast cancer who were enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial., Methods: Two physical parameters were assessed. Physical functioning was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire 1 year (T1) and 2 years (T2) after diagnosis. Physical activity was measured in metabolic equivalent of task (MET) hours/week at T1 and T2. Physical activity before diagnosis (T0) was assessed retrospectively at the T1 questionnaire. Patients were divided into three age groups: <60, 60-69, and ≥70 years. Decline in physical functioning was assessed using linear regression analysis. Differences in mean values of physical activity levels were calculated using repeated-measures one-way analysis of variance., Results: A total of 431 patients were included for analysis. In all age groups, physical activity levels at T1 and T2 were significantly lower than prediagnostic physical activity levels (T0) (p < .001 for all age groups). Age ≥70 years was independently associated with decline in physical functioning between T1 and T2 (β = -4.62, 95% confidence interval -8.73 to -0.51, p = .028)., Conclusion: Patients aged 70 years or older treated with breast surgery and adjuvant hormonal therapy did not improve between years 1 and 2 after diagnosis to the same extent as did younger patients., Implications for Practice: Although older patients constitute a large share of the breast cancer population, little is known about the effect and consequences of treatment of breast cancer in this specific age group. This study revealed that, unlike younger patients, older patients do not regain their physical abilities after surgical and adjuvant treatment for breast cancer. In older adults, the effect of treatment on physical functioning and independency could be more relevant than survival outcomes. Clinicians and older patients should be aware of the impact of treatment on physical functioning and prevent older patients from experiencing physical decline, which could lead to institutionalization and loss of independence. There is a need for age-specific guidelines that take into account the heterogeneity of the older population and for evidence-based treatment that focuses not only on cancer-specific outcomes but also on the consequences of treatment for physical and cognitive functioning and quality of life., (©AlphaMed Press.)

Introduction: Given increasing numbers of breast cancer survivors, there is an increased focus on quality of life and quality of care. This study aims to investigate whether clinical or patient reported outcomes are most important for perceived quality of care by breast cancer patients., Methods: Overall, 606 patients aged 18 years or older, who underwent breast cancer surgery 9-18 months ago in five hospitals in the Netherlands, were invited to complete an internet-based questionnaire. Patients were asked to judge a random selection of 24 patient profiles and choose which of 2 presented patients had received the best quality of care, using conjoint analysis. The individual relative importance (RI) for each outcome was estimated using Hierarchical Bayes Estimation, and averaged over all patients to assess which outcomes were most important., Results: Complete data were available for 350 patients (58%). Avoiding severe breast symptoms was most important for good quality of care according to patients (RI 23.22 [95% Confidence Interval (95% CI) 22.32-24.12]), followed by a 2 year longer disease free survival (18.30 [17.38-19.22]). However, the importance differed by age: younger patients (<50 years) assigned higher importance to longer disease free survival (21.99 [19.52-24.46]) than older patients (65 + years) (15.03 [13.88-16.18])., Conclusion: Avoiding severe breast symptoms rather than 2 year longer disease free survival is considered most important in our population of breast cancer patients for evaluation of quality of care. These data should thus be included in both information provision prior to treatment choices and post treatment quality of care evaluation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Intraoperative fluorescence imaging of the folate-receptor alpha (FRα) could support completeness of resection in cancer surgery. Feasibility of EC17, a FRα-targeting agent that fluoresces at 500nm, was demonstrated in a limited series of ovarian cancer patients. Our objective was to evaluate EC17 in a larger group of ovarian cancer patients. In addition, we assessed the feasibility of EC17 in patients with breast cancer., Methods: Two-to-three hours before surgery 0.1mg/kg EC17 was intravenously administered to 12 patients undergoing surgery for ovarian cancer and to 3 patients undergoing surgery for biopsy-proven FRα-positive breast cancer. The number of lesions/positive margins detected with fluorescence and concordance between fluorescence and tumor- and FRα-status was assessed in addition to safety and pharmacokinetics., Results: Fluorescence imaging in ovarian cancer patients allowed detection of 57 lesions of which 44 (77%) appeared malignant on histopathology. Seven out of these 44 (16%) were not detected with inspection/palpation. Histopathology demonstrated concordance between fluorescence and FRα- and tumor status. Fluorescence imaging in breast cancer patients, allowed detection of tumor-specific fluorescence signal. At the 500nm wavelength, autofluorescence of normal breast tissue was present to such extent that it interfered with tumor identification., Conclusions: FRα is a favorable target for fluorescence-guided surgery as EC17 produced a clear fluorescent signal in ovarian and breast cancer tissue. This resulted in resection of ovarian cancer lesions that were otherwise not detected. Notwithstanding, autofluorescence caused false-positive lesions in ovarian cancer and difficulty in discriminating breast cancer-specific fluorescence from background signal. Optimization of the 500nm fluorophore, will minimize autofluorescence and further improve intraoperative tumor detection., Competing Interests: PL is employed by On Target Laboratories LLC. The other authors declare no competing interests.

Folate receptor alpha (FRα) is known to be upregulated in a variety of cancers, including non-small cell lung cancer (NSCLC) and breast cancer. To ensure reliable implementation of diagnostic- and therapeutic agents, concordance of FRα expression between biopsy, primary tumor and metastases is important. Using immunohistochemistry (Mab 26B3.F2) these concordances were investigated in 60 NSCLC and 40 breast cancer patients. False positivity of FRα expression on breast and lung cancer biopsies was limited to less than 5%. In NSCLC, FRα expression was shown in 21/34 adenocarcinomas and 4/26 squamous cell carcinomas (SCC). Concordance of FRα expression between biopsy and primary tumor was achieved in respectively 83% and 91% of adenocarcinomas and SCCs. Approximately 80% of all local and distant metastases of NSCLC patients showed concordant FRα expression as their corresponding primary tumor. In breast cancer, FRα positivity was shown in 12/40 biopsies, 20/40 lumpectomies and 6/20 LN metastases, with concordance of 68% between biopsy and primary tumor and 60% between primary tumor and LN metastases. In conclusion, this study shows high concordance rates of FRα expression between biopsies and metastases compared to primary NSCLC and breast cancers, underscoring the applicability of FRα-targeted agents in these patients.

Introduction: It was recently proposed that the molecular breast tumor subtypes are differently distributed in the elderly breast cancer patients, and also lack prognostic value. Given the limited number of elderly patients in previous studies, the aim of this study was to determine the prognostic effect of the molecular intrinsic subtypes in a large older breast cancer population., Material and Method: Older breast cancer patients with invasive, non-metastatic breast cancer with tumor material available for immunohistochemical determination of Ki67, EGFR, CK5/6 and HER-2 were included. ER and PR expression was retrieved from the pathology report. Molecular subtypes were: Luminal A, Luminal B, ERBB2, Basal-like and Unclassified. Primary endpoint was Relapse Free Period (RFP), taking into account the competing risk of mortality, and adjusted for the most important patient, tumor and treatment characteristics. Secondary endpoint was Relative Survival (RS)., Results: Overall, 1362 patients were included. Patients with a Luminal A subtype had the lowest risk of recurrence (11% at 5 yrs). Patients with a Basal (24% at 5yrs) or ERBB2 (34% at 5yrs) molecular breast tumor subtype had the highest risk of recurrence. The ERBB2 subtype had the worst prognosis in terms of RFP (SHR 2.07, 95% CI 1.35-3.20; p = 0.001). The worst RS was again observed for the ERBB2 subtype (48% at 10 yrs). In multivariable analyses, the relative excess risk of death for all molecular subtypes was significantly worse compared to the Luminal A subtype., Conclusion: Molecular intrinsic breast tumor subtypes have significant prognostic value in the elderly population, even after taking competing mortality into account., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Studies to confirm the effect of acknowledged prognostic markers in older breast cancer patients are scarce. The aim of this study was to evaluate the prognostic value of HER-2 overexpression and PIK3CA mutations in older breast cancer patients. Female breast cancer patients aged 65 years or older, diagnosed between 1997 and 2004 in a geographical region in The Netherlands, with an invasive, non-metastatic tumour and tumour material available, were included in the study. The primary endpoint was relapse-free period and secondary endpoint was relative survival. Determinants were immunochemical HER-2 scores (0/1+, 2+ or 3+) and PIK3CA as a binary measure. Overall, 1698 patients were included, and 103 had a HER-2 score of 3+. HER-2 overexpression was associated with a higher recurrence risk (5 years recurrence risk 34 % vs. 12 %, adjusted p = 0.005), and a worse relative survival (10 years relative survival 48 % vs. 84 % for HER-2 negative; p = 0.004). PIK3CA mutations had no significant prognostic effect. We showed, in older breast cancer patients, that HER-2 overexpression was significantly associated with a worse outcome, but PIK3CA mutations had no prognostic effect. These results imply that older patients with HER-2 overexpressing breast cancer might benefit from additional targeted anti-HER-2 therapy.

Background: Signaling via the Insulin-like Growth Factor type 1 Receptor (IGF1R) plays a crucial role in cancer development. In breast cancer (BC), IGF1R and estrogen receptor expression are correlated. In this current study we explored the hypothesis that postmenopausal hormone receptor positive (HR+ve) BC patients with high IGF1R tumor expression still have estrogen driven IGF1R stimulated tumor growth when treated with tamoxifen, resulting in detrimental clinical outcome compared to patients treated with exemestane. Additionally, we assessed the added value of metformin as this drug may lower IGF1R stimulation., Methods: Of 2,446 Dutch TEAM patients, randomized to either exemestane for 5 years or sequential treatment (tamoxifen for 2-3 years followed by exemestane for another 3-2 years) tumor tissue microarray sections were immunohistochemically stained for IGF1R. Overall Survival (OS), Breast Cancer specific Survival (BCSS) and Relapse-Free Survival (RFS) were assessed in patient subgroups with low and high IGF1R expression, and in patients with or without metformin use., Results: High IGF1R tumor expression was significantly associated with exemestane therapy for RFS (Hazard Ratio (HR) 0.74, 95% Confidence Interval (CI) 0.58-0.95, p = 0.02). In addition, the combination of metformin with exemestane resulted in improved efficacy, yielding a 5-yrs RFS of 95% (HR 0.32, 95% CI 0.10-1.00, p = 0.02, compared to sequential treatment). No relation was observed in tumors with low IGF-1R expression., Conclusion: This study suggests IGF1R as a potential biomarker of improved clinical outcome in HR+ve BC patients treated with exemestane. Adding metformin to exemestane treatment may add to this effect., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Background: Predicting breast cancer outcome in older patients is challenging, as it has been shown that the available tools are not accurate in older patients. The PREDICT tool may serve as an alternative tool, as it was developed in a cohort that included almost 1800 women aged 65 years or over. The aim of this study was to assess the validity of the online PREDICT tool in a population-based cohort of unselected older patients with breast cancer., Methods: Patients were included from the population-based FOCUS-cohort. Observed 5- and 10-year overall survival were estimated using the Kaplan-Meier method, and compared with predicted outcomes. Calibration was tested by composing calibration plots and Poisson Regression. Discriminatory accuracy was assessed by composing receiver-operator-curves and corresponding c-indices., Results: In all 2012 included patients, observed and predicted overall survival differed by 1.7%, 95% confidence interval (CI)=-0.3-3.7, for 5-year overall survival, and 4.5%, 95% CI=2.3-6.6, for 10-year overall survival. Poisson regression showed that 5-year overall survival did not significantly differ from the ideal line (standardised mortality ratio (SMR)=1.07, 95% CI=0.98-1.16, P=0.133), but 10-year overall survival was significantly different from the perfect calibration (SMR=1.12, 95% CI=1.05-1.20, P=0.0004). The c-index for 5-year overall survival was 0.73, 95% CI=0.70-0.75, and 0.74, 95% CI=0.72-0.76, for 10-year overall survival., Conclusions: PREDICT can accurately predict 5-year overall survival in older patients with breast cancer. Ten-year predicted overall survival was, however, slightly overestimated.

Background: Serum levels of 25-OH vitamin D3 (vitamin D) have been shown to be prognostic for disease-free survival in patients with breast cancer. We investigated the predictive value of these levels for pathological response after neoadjuvant chemotherapy in patients with breast cancer taking part in the NEOZOTAC phase-III trial. Additionally, the effect of chemotherapy on vitamin D levels was studied., Materials and Methods: Serum vitamin D was measured at baseline and before the last cycle of chemotherapy. The relationship between these measurements and clinical outcome, as defined by pathological complete response in breast and lymph nodes (pCR) was examined., Results: Baseline and end of treatment vitamin D data were available in 169 and 91 patients, respectively. Median baseline vitamin D values were 58.0 nmol/L. In patients treated with chemotherapy only, serum vitamin D levels decreased during neoadjuvant chemotherapy (median decrease of 16 nmol/L, P = 0.003). The prevalence of vitamin D levels < 50 nmol/L increased from 38.3% at baseline to 55.9% after chemotherapy. In the total population, baseline and end of therapy vitamin D levels were not related to pathological response. No associations were found between pCR and vitamin D level changes., Conclusion: The significant decrease in vitamin D post-neoadjuvant chemotherapy suggests that vitamin D levels should be monitored and in case of decrease of vitamin D levels, correction may be beneficial for skeletal health and possibly breast cancer outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Context: Hormone receptors HER2/neu and Ki-67 are markers of residual risk in early breast cancer. An algorithm (IHC4) combining these markers may provide additional information on residual risk of recurrence in patients treated with hormone therapy., Objective: To independently validate the IHC4 algorithm in the multinational Tamoxifen Versus Exemestane Adjuvant Multicenter Trial (TEAM) cohort, originally developed on the trans-ATAC (Arimidex, Tamoxifen, Alone or in Combination Trial) cohort, by comparing 2 methodologies., Design: The IHC4 biomarker expression was quantified on TEAM cohort samples (n = 2919) by using 2 independent methodologies (conventional 3,3'-diaminobezidine [DAB] immunohistochemistry with image analysis and standardized quantitative immunofluorescence [QIF] by AQUA technology). The IHC4 scores were calculated by using the same previously established coefficients and then compared with recurrence-free and distant recurrence-free survival, using multivariate Cox proportional hazards modeling., Results: The QIF model was highly significant for prediction of residual risk (P < .001), with continuous model scores showing a hazard ratio (HR) of 1.012 (95% confidence interval [95% CI]: 1.010-1.014), which was significantly higher than that for the DAB model (HR: 1.008, 95% CI: 1.006-1.009); P < .001). Each model added significant prognostic value in addition to recognized clinical prognostic factors, including nodal status, in multivariate analyses. Quantitative immunofluorescence, however, showed more accuracy with respect to overall residual risk assessment than the DAB model., Conclusions: The use of the IHC4 algorithm was validated on the TEAM trial for predicting residual risk in patients with breast cancer. These data support the use of the IHC4 algorithm clinically, but quantitative and standardized approaches need to be used.

An important consideration in studies that use cause-specific endpoints such as cancer-specific survival or disease recurrence is that risk of dying from another cause before experiencing the event of interest is generally much higher in older patients. Such competing events are of major importance in the design and analysis of studies with older patients, as a patient who dies from another cause before the event of interest cannot reach the endpoint. In this Commentary, we present several clinical examples of research questions in a population-based cohort of older breast cancer patients with a high frequency of competing events and discuss implications of choosing models that deal with competing risks in different ways. We show that in populations with high frequency of competing events, it is important to consider which method is most appropriate to estimate cause-specific endpoints. We demonstrate that when calculating absolute cause-specific risks the Kaplan-Meier method overestimates risk of the event of interest and that the cumulative incidence competing risks (CICR) method, which takes competing risks into account, should be used instead. Two approaches are commonly used to model the association between prognostic factors and cause-specific survival: the Cox proportional hazards model and the Fine and Gray model. We discuss both models and show that in etiologic research the Cox Proportional Hazards model is recommended, while in predictive research the Fine and Gray model is often more appropriate. In conclusion, in studies with cause-specific endpoints in populations with a high frequency of competing events, researchers should carefully choose the most appropriate statistical method to prevent incorrect interpretation of results., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

Objective: The aim of this study is to assess age-specific compliance to quality indicators (QIs) regarding the treatment of breast cancer as defined by European Society of Breast Cancer Specialists (EUSOMA) for patients across Europe., Methods: All patients entered into this study were affected by in situ or invasive breast cancer, diagnosed and treated between 2003 and 2012 at 27 Breast Units across Europe, who were entered into the EUSOMA database. Patients were categorised according to age; compliance to thirteen QIs was assessed for each age group and per time period (2003-2007 and 2008-2012). Compliance to QIs was tested by multivariable logistic regression models adjusted for breast unit, incidence year and tumour characteristics., Results: Overall, 41,871 patients with a mean age of 59.6years were available for analysis. The highest compliance was reached for patients aged 55-64years and in the time period 2008-2012, whilst the lowest compliance was observed for women aged over 74 or under 40years and in the earlier time period. In multivariable logistic regression models, a significant difference between age categories was shown for 12 out of 13 QIs (P<0.001). Compliance to the QIs for patients aged ⩾75years was significantly lower when compared to patients aged 55-64years for ten QIs, whilst for patients in the youngest age group this was true for seven QIs., Conclusion: In conclusion, we found that among the 27 included breast units across Europe, compliance to QIs for breast cancer treatment is often lower in the youngest and oldest breast cancer patients, with a tendency to overtreatment in the youngest patients, and to under-treatment in the elderly., (Copyright © 2015. Published by Elsevier Ltd.)

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 < 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 I-II breast cancer patients and the general population, 6-8.5 years after diagnosis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: The tumor-associated stroma is of importance for tumor progression and is generally accepted to have a significant influence on patient prognosis. However, little is known regarding specific features of tumor-associated stromal tissues and response to (neoadjuvant) chemotherapy. This study investigated the predictive value of extracellular matrix organization on response to chemotherapy in patients treated in the NEOZOTAC trial., Methods: Stromal organisation was analyzed via a simple method using image analysis software on hematoxylin and eosin (H&E)-stained slides from primary tumor biopsies collected as part of the NEOZOTAC trial. Heidenhain's AZAN trichrome-stained slides were also analyzed for comparison of collagen evaluation. Sections were stained for phospho-Smad2 (pS2) in order to determine the relationship of TGF-β signaling with stromal organization., Results: A statistically significant relationship was observed between stroma consisting of organised collagen and pathological response to neoadjuvant chemotherapy (Odds Ratio 0.276, 95%CI 0.124-0.614, P = 0.002). This parameter was also related to ER-status (P = 0.003), clinical tumor -status (P = 0.041), nodal status (P = 0.029) and pS2 status (P = 0.025). Correlation between stromal organisation determined on H&E-stained and AZAN-stained tissue sections was high (Pearson's correlation coefficient = 0.806)., Conclusion: Intratumoral stromal organisation determined using pre-treatment breast cancer biopsies was related to pathological response to chemotherapy. This parameter might play a role in the management of breast cancer for identifying those patients that are likely to benefit from neoadjuvant chemotherapy., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Background: Despite the increased attention for assessing the effectiveness of implementation strategies, most implementation studies provide little or no information on its associated costs. The focus of the current study was to provide a detailed report of the resource use and costs associated with implementation of a short stay programme for breast cancer surgery in four Dutch hospitals., Methods: The analysis was performed alongside a multi-centre implementation study. The process of identification, measurement and valuation of the implementation activities was based on recommendations for the design, analysis and reporting of health technology assessments. A scoring form was developed to prospectively determine the implementation activities at professional and implementation expert level. A time horizon of 5 years was used to calculate the implementation costs per patient., Results: Identified activities were consisted of development and execution of the implementation strategy during the implementation project. Total implementation costs over the four hospitals were €83.293. Mean implementation costs, calculated for 660 patients treated over a period of 5 years, were €25 per patient. Subgroup analyses showed that the implementation costs ranged from €3.942 to €32.000 on hospital level. From a local hospital perspective, overall implementation costs were €21 per patient, after exclusion of the costs made by the expert centre., Conclusions: We provided a detailed case description of how implementation costs can be determined. Notable differences in implementation costs between hospitals were observed., Isrctn: ISRCTN77253391.

Circulating tumor cells (CTC) are detected by the CellSearch System in 20% to 25% of patients with primary breast cancer (pBC). To improve CTC detection, we investigated melanoma cell adhesion molecule (MCAM) as enrichment marker next to epithelial cell adhesion molecule (EpCAM) and tested the clinical relevance of MCAM-positive CTCs in patients with HER2-negative stage II/III pBC starting neoadjuvant chemotherapy (NAC) in the NEOZOTAC trial. Using the CellSearch System, EpCAM-positive and MCAM-positive CTCs were separately enriched from 7.5 mL blood, at baseline and after the first NAC cycle. Circulating endothelial cells (CEC) were measured using flow cytometry. Primary objective was to improve the CTC detection rate to ≥ 40% combining EpCAM/MCAM. Correlations of CTC and CEC counts and pathologic complete response (pCR) were also explored. At baseline, we detected EpCAM-positive and MCAM-positive CTCs in 12 of 68 (18%) and 8 of 68 (12%) patients, respectively. After one cycle, this was 7 of 44 (16%) and 7 of 44 (16%) patients, respectively. The detection rate improved from 18% at baseline and 16% after one cycle with EpCAM to 25% (P = 0.08) and 30% (P = 0.02), respectively, with EpCAM/MCAM. No patients with MCAM-positive CTCs versus 23% of patients without MCAM-positive CTCs at baseline achieved pCR (P = 0.13). EpCAM-positive CTCs and CEC counts were not correlated to pCR. Combined EpCAM/MCAM CellSearch enrichment thus increased the CTC detection rate in stage II/III pBC. We found no associations of CTC and CEC counts with pCR to NAC. The clinical relevance of MCAM-positive CTCs deserves further study., (©2014 American Association for Cancer Research.)

Background: Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial., Material and Methods: Analogue mammograms of selected TEAM participants before start, and after one and two (and if available after three) years of adjuvant endocrine therapy were collected centrally and reviewed. Study endpoints were change in breast density over time, and correlations between breast density and locoregional recurrence (LRR), distance recurrence (DR), and contralateral breast cancer (CBC)., Results: Mammograms of 378 patients (181 tamoxifen, 197 exemestane) were included in the current per protocol analyses. Baseline breast density was low (breast density score<50% in 75% of patients) and not different between patients randomised to exemestane or tamoxifen (coefficient 0.16, standard error 0.17). Breast density did not change during treatment in exemestane (p=0.25) or tamoxifen users (p=0.59). No relation was observed between breast density and the occurrence of a LRR [hazards ratio (HR) 0.87, 95% CI 0.45-1.68, p=0.67], a DR (HR 1.02, 95% CI 0.77-1.35, p=0.90), or CBC (HR 1.31, 95% CI 0.63-2.72, p=0.48)., Conclusion: The in general low breast density score in early postmenopausal breast cancer patients did not substantially change over time, and this pattern was not different between tamoxifen and exemestane users. Breast density was not a predictive marker for efficacy of adjuvant endocrine therapy.

The optimal duration and regimen of adjuvant hormonal therapy for premenopausal and postmenopausal patients with hormone receptor positive early breast cancer has not yet been established. This review will give an overview of published and ongoing studies concerning extended endocrine treatment. Most of the currently published studies are based on the adjuvant treatment regime of 5 years tamoxifen, which has been proven to be inferior compared to aromatase inhibitor (AI)-containing regimes. Therefore, until today, there is no clear evidence for the extension of endocrine therapy after upfront AI-based adjuvant treatment regimes. Multiple clinical trials, which will be discussed in this review, are ongoing to elucidate on this matter. We emphasize the need for tailoring of extended adjuvant endocrine treatment. The quest for predictive biomarkers, which are currently being investigated in the context of decision-making whether or not to start adjuvant chemotherapy, should be expanded to include the feasibility of extended endocrine treatment based on these markers. By tailoring the extension of endocrine treatment, overtreatment, side effects and unnecessary costs will be prevented., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Solid evidence of treatment effects in older women with breast cancer is lacking, as they are generally underrepresented in randomized clinical trials on which guideline recommendations are based. An alternative way to study treatment effects in older patients could be to use data from observational studies. However, using appropriate methods in analyzing observational data is a key condition in order to draw valid conclusions, as directly comparing treatments generally results in biased estimates due to confounding by indication. The aim of this systematic review was to investigate the methods that have been used in observational studies that assessed the effects of breast cancer treatment on survival, breast cancer survival and recurrence in older patients (aged 65 years and older). Studies were identified through systematic review of the literature published between January 1st 2009 and December 13th 2013 in the PubMed database and EMBASe. Finally, 31 studies fulfilled the inclusion criteria. Of these, 22 studies directly compared two treatments. Fifteen out of these 22 studies addressed the problem of confounding by indication, while seven studies did not. Nine studies used some form of instrumental variable analysis. In conclusion, the vast majority of observational studies that investigate treatment effects in older breast cancer patients compared treatments directly. These studies are therefore likely to be biased. Observational research will be essential to improve treatment and outcome of older breast cancer patients, but the use of accurate methods is essential to draw valid conclusions from this type of data., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Forty percent of breast cancers occur among older patients. Unfortunately, there is a lack of evidence for treatment guidelines for older breast cancer patients. The aim of this study is to compare treatment strategy and relative survival for operable breast cancer in the elderly between The Netherlands and Ireland., Material and Methods: From the Dutch and Irish national cancer registries, women aged ≥65 years with non-metastatic breast cancer were included (2001-2009). Proportions of patients receiving guideline-adherent locoregional treatment, endocrine therapy, and chemotherapy were calculated and compared between the countries by stage. Secondly, 5-year relative survival was calculated by stage and compared between countries., Results: Overall, 41,055 patients from The Netherlands and 5,826 patients from Ireland were included. Overall, more patients received guideline-adherent locoregional treatment in The Netherlands, overall (80% vs. 68%, adjusted p<0.001), stage I (83% vs. 65%, p<0.001), stage II (80% vs. 74%, p<0.001) and stage III (74% vs. 57%, P<0.001) disease. On the other hand, more systemic treatment was provided in Ireland, where endocrine therapy was prescribed to 92% of hormone receptor-positive patients, compared to 59% in The Netherlands. In The Netherlands, only 6% received chemotherapy, as compared 24% in Ireland. But relative survival was poorer in Ireland (5 years relative survival 89% vs. 83%), especially in stage II (87% vs. 85%) and stage III (61% vs. 58%) patients., Conclusion: Treatment for older breast cancer patients differed significantly on all treatment modalities between The Netherlands and Ireland. More locoregional treatment was provided in The Netherlands, and more systemic therapy was provided in Ireland. Relative survival for Irish patients was worse than for their Dutch counterparts. This finding should be a strong recommendation to study breast cancer treatment and survival internationally, with the ultimate goal to equalize the survival rates for breast cancer patients across Europe.

Purpose: Diffuse optical spectroscopy (DOS) has the potential to enable monitoring of tumor response during chemotherapy, particularly in the early stages of treatment. This study aims to assess feasibility of DOS for monitoring treatment response in HER2-negative breast cancer patients receiving neoadjuvant chemotherapy (NAC) and compare DOS with tumor response assessment by MRI., Experimental Design: Patients received NAC in six cycles of 3 weeks. In addition to standard treatment monitoring by dynamic contrast enhanced MRI (DCE-MRI), DOS scans were acquired after the first, third, and last cycle of chemotherapy. The primary goal was to assess feasibility of DOS for early assessment of tumor response. The predictive value of DOS and DCE-MRI compared with pathologic response was assessed., Results: Of the 22 patients, 18 patients had a partial or complete tumor response at pathologic examination, whereas 4 patients were nonresponders. As early as after the first chemotherapy cycle, a significant difference between responders and nonresponders was found using DOS (HbO2 86% ± 25 vs. 136% ± 25, P = 0.023). The differences between responders and nonresponders continued during treatment (halfway treatment, HbO2 68% ± 22 vs. 110% ± 10, P = 0.010). Using DCE-MRI, a difference between responders and nonresponders was found halfway treatment (P = 0.005) using tumor volume measurement calculations., Conclusions: DOS allows for tumor response assessment and is able to differentiate between responders and nonresponders after the first chemotherapy cycle and halfway treatment. In this study, DOS was equally effective in predicting tumor response halfway treatment compared with DCE-MRI. Therefore, DOS may be used as a novel imaging modality for (early) treatment monitoring of NAC., (©2014 American Association for Cancer Research.)

Background: Older women are more likely to be diagnosed with primary metastasised breast cancer than their younger counterparts. Evolving treatment strategies of metastasised breast cancer have resulted in improved survival in younger patients, but it remains unclear if this improvement has occurred in older patients as well. The aim of this study was to assess changes in treatment strategies over time in relation to overall and relative survival of older patients compared to younger patients with primary metastasised breast cancer., Methods: All patients with a breast cancer diagnosis and distant metastases at first presentation (stage IV), between 1990 and 2012, were selected from the Netherlands Cancer Registry. Changes in treatment over time per age-group (<65 years, 65-75 years and >75 years) were assessed using logistic regression. Overall survival over time was calculated using Cox Regression Models and relative survival was assessed using the Ederer II method., Results: Overall, 14,310 patients were included. Treatment strategies have strongly changed in the past twenty years; especially the use of chemotherapy has increased (P<0.001 in all age-groups). Overall survival of patients <65 has significantly improved (Hazard Ratio (HR) per year 0.98, 95% Confidence Interval (CI) 0.98-0.99, P<0.001), but the survival of older patients has not improved (HR 1.00, 95% CI 0.99-1.01, P=0.86 for patients aged 65-75 and HR 1.00, 95% CI 1.00-1.01, P=0.46 for patients aged >75). Similarly, relative survival has improved in patients <65 but not in women aged 65-75 and >75., Conclusion: Overall and relative survival of older patients with metastasised breast cancer at first presentation have not improved in recent years in contrast with the survival of younger patients, despite increased treatment with chemotherapy for women of all ages. Future studies should focus on stratification models that can be used to predict which patients may benefit from specific treatment options., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Previous studies have shown that breast cancer survival decreases with increasing age among older patients who participate in trials. However, trial participants differ from patients in the general population. Therefore, the aim of this study was to evaluate the association between age and breast cancer outcome in an unselected group of older breast cancer patients., Methods: We included all older (65 years and older) consecutive breast cancer patients, diagnosed between 1997 and 2004 from a geographically defined area in the Netherlands. Primary outcome was relative survival and the secondary endpoint was breast cancer recurrence. These outcomes were compared between two age-categories (65-74 years and ≥75 years)., Results: Five-year relative survival was 91.9% in patients aged 65-74 years, and 84.3% in patients aged ≥75 years. This corresponded with a higher excess risk of death in patients aged ≥75 years as compared to patients aged 65-74 years (multivariable relative excess risk of death: 1.73 (95% CI 1.20-2.49)). The risks of locoregional recurrence, distant recurrence and contralateral breast cancer were similar in both age-categories., Conclusions: Breast cancer survival deteriorates with increasing age among unselected older breast cancer patients. Of note, this was not accompanied by an increased risk of recurrence. This study shows that not only in relatively healthy patients who participate in a trial, but in all older breast cancer patients, outcome deteriorates with increasing age. These findings urge the need for age-specific breast cancer studies, in order to obtain evidence-based medicine in this large and heterogeneous group of patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Identification of patients who are at increased risk for contralateral breast cancer is essential to determine which patients should be routinely screened for contralateral breast cancer using MRI. The aim of this study was to assess the association of age and tumor morphology with contralateral breast cancer incidence in a large, nationwide population-based study in the Netherlands. All patients with breast cancer stage I-III, diagnosed between 1989 and 2009, were selected from the Netherlands Cancer Registry. The association between contralateral breast cancer risk with tumor morphology and age was assessed using competing-risk regression according to Fine & Gray. Overall, 194,898 patients were included. In multivariable analyses, lobular tumors were significantly associated with an increased risk of contralateral breast cancer within 6 months (cumulative incidence 1.9 %, subdistribution hazard ratio (SHR) 1.17, 95 % confidence interval (CI) 1.06-1.30 compared with 1.3 % in ductal tumors, p = 0.002). Age was also associated with an increased risk of contralateral breast cancer within 6 months (SHR 2.34, 95 % CI 2.08-2.62, p < 0.002 for patients over the age of 75 as compared to patients younger than 50 years). The absolute risk of contralateral breast cancer within 6 months is only slightly increased in patients with a lobular tumor and older patients. In our view, this small increased risk does not justify standard use of preoperative MRI based on tumor morphology or age alone. We propose a more personalized strategy in which additional risk factors (family history, prognosis of primary tumor, and others) may play a role.

Evidence exists for an immunomodulatory effect of endocrine therapy in hormone receptor-positive (HR+ve) breast cancer (BC). Therefore, the aim of this study was to define the prognostic and predictive value of tumor immune markers and the tumor immune profile in HR+ve BC, treated with different endocrine treatment regimens. 2,596 Dutch TEAM patients were treated with 5 years of adjuvant hormonal treatment, randomly assigned to different regimens: 5 years of exemestane or sequential treatment (2.5 years of tamoxifen-2.5 years of exemestane). Immunohistochemistry was performed for HLA class I, HLA-E, HLA-G, and FoxP3. Tumor immune subtypes (IS) (low, intermediate & high immune susceptible) were determined by the effect size of mono-immune markers on relapse rate. Patients on sequential treatment with high level of tumor-infiltrating FoxP3+ cells had significant (p = 0.019, HR 0.729, 95% CI 0.560-0.949) better OS. Significant interaction for endocrine treatment and FoxP3+ presence was seen (OS p < 0.001). Tumor IS were only of prognostic value for the sequentially endocrine-treated patients (RFP: p = 0.035, HR intermediate IS 1.420, 95% CI 0.878-2.297; HR low IS 1.657, 95% CI 1.131-2.428; BCSS: p = 0.002, HR intermediate IS 2.486, 95% CI 1.375-4.495; HR low IS 2.422, 95% CI 1.439-4.076; and OS: p = 0.005, HR intermediate IS 1.509, 95% CI 0.950-2.395; HR low IS 1.848, 95% CI 1.277-2.675). Tregs and the tumor IS presented in this study harbor prognostic value for sequentially endocrine-treated HR+ve postmenopausal BC patients, but not for solely exemestane-treated patients. Therefore, these markers could be used as a clinical risk stratification tool to guide adjuvant treatment in this BC population.

Aim: SNPs may be associated with (side) effects of chemotherapy and may be useful as biomarkers to predict febrile neutropenia., Patients & Methods: 187 DNA samples extracted from formalin-fixed paraffin-embedded tissue from patients with stage II/III HER2-negative breast cancer were genotyped., Results: Candidate SNPs were selected and explored for association with febrile neutropenia and/or pathological complete response. TT genotype of 388 C>T in FGFR4 (rs351855) had a tendency toward higher incidence of febrile neutropenia during neoadjuvant chemotherapy, compared with the CT (p = 0.383) genotype and compared with the CC genotype (p = 0.068)., Conclusion: The TT genotype of 388 C>T FGFR4 may be related to incidence of febrile neutropenia during neoadjuvant TAC (docetaxel, doxorubicin, cyclophosphamide) chemotherapy and is possibly useful as a patient-related risk factor when assessing febrile neutropenia risk. Original submitted 23 January 2015; Revision submitted 26 May 2015.

This side study investigated the effect of chemotherapy on thyroid function and the extent to which it can predict pathological complete response (pCR) in patients with early breast cancer taking part in NEOZOTAC phase III trial, randomizing between neoadjuvant chemotherapy with or without additional zoledronic acid. Moreover, we examined the impact of thyroid function on toxicity. Serum samples of 38 patients were available for analyses. Free thyroxin (fT4) and thyroid stimulating hormone (TSH) levels were compared between baseline and before the 6th cycle and between subjects with and without pCR. The relation between toxicity and the variation in fT4 and TSH levels during chemotherapy was tested. Samples at baseline and before the 6th cycle were available for 31 and 21 patients, respectively. The mean baseline fT4 level was 16.0 pmol/L and TSH level 1.11 mU/L, and these did not differ between both arms at each time point. During six cycles of chemotherapy, fT4 levels decreased (p = 0.0001), and TSH levels increased significantly (p = 0.019). Interestingly, the decrease of fT4 was significantly greater in patients without nausea, vomiting, or neuropathy, than in patients with those side effects (p = 0.037, p = 0.043, and p = 0.050, respectively). Baseline TSH levels tended to be higher in patients with pCR (p = 0.035 univariate analysis and p = 0.074 multivariate analysis). Chemotherapy blunts thyroid function, which was associated with less side effects. These data urge further evaluation of the effects of thyroid function on toxicity and outcome of breast cancer therapy.

Background: We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial., Methods: The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling was performed over the intervals of 0-5 years and >5 years., Results: We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R(2) between 5 and 6% and increases in D-statistic between 0.16 and 0.21., Conclusions: Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy.

As the number of breast cancer survivors increases, this study prospectively examined whether tailored follow-up with differentiated number of visits per risk group, based on a prognostic index for local recurrence, is feasible and acceptable for patients and professionals. Between March 2007 and March 2010, 180 breast cancer patients (pT1-2N0-2cM0) were included. Primary endpoint was feasibility of tailored follow-up, based on the number of follow-up visits, patient satisfaction, anxiety and attitude towards follow-up. Secondary endpoints were reasons for visits, incidence, time to detection of local recurrences and the use of alternative care. In the second and third year of follow-up, the results show a 22% reduction in visits per patient in the low-risk group compared to the intermediate-risk group; 2.8 versus 3.6 visits. The majority of interval visits in both groups was initiated by the professional. No significant differences were found in attitude towards follow-up, patient satisfaction, anxiety and depression, alternative health care use or local recurrences between the risk groups. In conclusion, implementation of a tailored follow-up programme with decreased number of visits for low-risk patients is feasible and acceptable to patients. Appointing one coordinating professional, possibly a nurse practitioner, could further reduce the number of follow-up visits., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: In breast cancer studies, many different endpoints are used. Definitions are often not provided or vary between studies. For instance, "local recurrence" may include different components in similar studies. This limits transparency and comparability of results. This project aimed to reach consensus on the definitions of local event, second primary breast cancer, regional and distant event for breast cancer studies., Methods: The RAND-UCLA Appropriateness method (modified Delphi method) was used. A Consensus Group of international breast cancer experts was formed, including representatives of all involved clinical disciplines. Consensus was reached in two rounds of online questionnaires and one meeting., Results: Twenty-four international breast cancer experts participated. Consensus was reached on 134 items in four categories. Local event is defined as any epithelial breast cancer or ductal carcinoma in situ (DCIS) in the ipsilateral breast, or skin and subcutaneous tissue on the ipsilateral thoracic wall. Second primary breast cancer is defined as epithelial breast cancer in the contralateral breast. Regional events are breast cancer in ipsilateral lymph nodes. A distant event is breast cancer in any other location. Therefore, this includes metastasis in contralateral lymph nodes and breast cancer involving the sternal bone. If feasible, tissue sampling of a first, solitary, lesion suspected for metastasis is highly recommended., Conclusion: This project resulted in consensus-based event definitions for classification of recurrence in breast cancer research. Future breast cancer research projects should adopt these definitions to increase transparency. This should facilitate comparison of results and conducting reviews as well as meta-analysis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects., Methods: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612., Findings: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years., Interpretation: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity., Funding: EORTC Charitable Trust., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Studies suggest that MRI is an accurate means for assessing tumor size after neoadjuvant chemotherapy (NAC). However, accuracy might be dependent on the receptor status of tumors. MRI accuracy for response assessment after homogenous NAC in a relative large group of patients with stage II/III HER2-negative breast cancer has not been reported before., Methods: 250 patients from 26 hospitals received NAC (docetaxel, adriamycin and cyclophosphamide) in the context of the NEOZOTAC trial. MRI was done after 3 cycles and post-NAC. Imaging (RECIST 1.1) and pathological (Miller and Payne) responses were recorded. Accuracy measures were calculated and MRI and pathologically assessed tumor sizes were correlated. Tumor size over- and underestimation were quantified., Results: Accuracy of MRI for determining pathological complete response (pCR) was 76%. The ROC-curve of MRI response and pCR had an area under the curve value of 0.63 (95% C.I. 0.52-0.74). The correlation coefficient of MRI and histopathological tumor measurements was 0.46 (p < 0.001). Correlations were different for ER-positive (r = 0.40, p < 0.001) and ER-negative (r = 0.76, p < 0.001) breast tumors. MRI under- and overestimated the tumor size in 47% and 40% of all patients. In cases of substantial tumor size underestimation (>2 cm), surgical margins were more often tumor positive compared to the rest of the patients (33% vs.12%, p = 0.005)., Conclusion: MRI measurements correlated moderately with tumor size on the surgical specimen. Only in ER-negative breast tumors, MRI tumor sizes correlated sufficiently with residual tumor size on the pathological specimen. Therefore, post-NAC MRI should be interpreted with caution., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Older patients with breast cancer are often not treated in accordance with guidelines. With the emergence of endocrine therapy, omission of surgery can be considered in some patients. The aim of this population-based study was to investigate time trends in surgical treatment between 1995 and 2011, and to evaluate the effects of omitting surgery on overall and relative survival in older patients with resectable breast cancer., Methods: Patients aged 75  years and older with stage I-III breast cancer diagnosed between 1995 and 2011 were selected from the Netherlands Cancer Registry. Time trends of all treatment modalities were evaluated using linear regression models. Changes in overall survival were calculated by Cox regression. Relative survival was calculated using the Ederer II method., Results: Overall, 26 292 patients were included. The proportion of patients receiving surgical treatment decreased significantly, from 90·8 per cent in 1995 to 69·9 per cent in 2011 (P < 0·001). Multivariable analysis showed that overall survival did not change over time (hazard ratio 1·00 (95 per cent confidence interval (c.i.) 0·99 to 1·00) per year); nor did relative survival (relative excess risk 1·00 (0·98 to 1·02) per year)., Conclusion: Omission of surgery has become more common in older patients with breast cancer during the past 15 years in the Netherlands, but this has not altered overall or relative survival., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Purpose: Deregulation of key PI3K/AKT pathway genes may contribute to endocrine resistance in breast cancer (BC). PIK3CA is the most frequently mutated gene in luminal BC (35%); however, the effect of mutations in helical versus kinase domains remains controversial. We hypothesize that improved outcomes occur in patients with estrogen receptor–positive (ER positive) BC receiving endocrine therapy and possessing PIK3CA mutations., Materials and Methods: DNA was extracted from 4,540 formalin-fixed paraffin-embedded BC samples from the Exemestane Versus Tamoxifen-Exemestane pathology study. Mutational analyses were performed for 25 mutations (PIK3CAx10, AKT1x1, KRASx5, HRASx3, NRASx2 and BRAFx4)., Results: PIK3CA mutations were frequent (39.8%), whereas RAS/RAF mutations were rare (1%). In univariable analyses PIK3CA mutations were associated with significantly improved 5-year distant relapse-free survival (DRFS; HR, 0.76; 95% CI, 0.63 to 0.91; P = .003). However, a multivariable analysis correcting for known clinical and biologic prognostic factors failed to demonstrate that PIK3CA mutation status is an independent prognostic marker for DRFS (HR, 0.92; 95% CI, 0.75 to 1.12; P = .4012). PIK3CA mutations were more frequent in low-risk luminal BCs (e.g., grade 1 nodev 3, node-negative v -positive), confounding the relationship between mutations and outcome., Conclusion: PIK3CA mutations are present in approximately 40% of luminal BCs but are not an independent predictor of outcome in the context of endocrine therapy, whereas RAS/RAF mutations are rare inluminal BC. A complex relationship between low-risk cancers and PIK3CA mutations was identified. Although the PI3K/AKT pathway remains a viable therapeutic target as the result of ahigh mutation frequency, PIK3CA mutations do not seem to affect residual risk following treatment with endocrine therapy.

Background: Physical activity has been related to improved breast cancer outcomes. Especially in the older breast cancer population, physical activity may be important because old age is associated with comorbidities and decreased physical function. The purpose of this study was to investigate the relation between physical activity and overall survival, breast cancer-specific survival, and recurrence in several age groups of postmenopausal breast cancer patients., Methods: The Tamoxifen Exemestane Adjuvant Multinational Lifestyle study was a side study of the Tamoxifen Exemestane Adjuvant Multinational trial and prospectively investigated lifestyle habits of postmenopausal, hormone receptor-positive breast cancer patients. The relations between prediagnosis and postdiagnosis physical activity and overall survival, breast cancer-specific survival, and recurrence-free survival were assessed with Cox regression and competing risk regression models., Results: Among 521 patients, high levels of physical activity before and after the diagnosis were associated with better overall survival (the multivariate hazard ratios were 0.50 [95% confidence interval = 0.26-0.98] and 0.57 (95% confidence interval = 0.26-1.40] for patients who were very active before and after the diagnosis, respectively, in comparison with inactive patients). This was most evident in patients who were 65 years old or older. Physical activity was not significantly associated with breast cancer-specific survival or the relapse-free period., Conclusions: Overall survival was better for patients who were active before and after the diagnosis. In contrast with previous studies, breast cancer survival and the risk of recurrence were not significantly associated with physical activity. These findings confirmed the need for more studies investigating the use of physical activity to supplement breast cancer treatment in older patients., (© 2014 American Cancer Society.)

Objective: To assess the incidence of early stage and advanced stage breast cancer before and after the implementation of mass screening in women aged 70-75 years in the Netherlands in 1998., Design: Prospective nationwide population based study., Setting: National cancer registry, the Netherlands., Participants: Patients aged 70-75 years with a diagnosis of invasive or ductal carcinoma in situ breast cancer between 1995 and 2011 (n=25,414). Incidence rates were calculated using population data from Statistics Netherlands., Main Outcome Measure: Incidence rates of early stage (I, II, or ductal carcinoma in situ) and advanced stage (III and IV) breast cancer before and after implementation of screening. Hypotheses were formulated before data collection., Results: The incidence of early stage tumours significantly increased after the extension for implementation of screening (248.7 cases per 100,000 women before screening up to 362.9 cases per 100,000 women after implementation of screening, incidence rate ratio 1.46, 95% confidence interval 1.40 to 1.52, P<0.001). However, the incidence of advanced stage breast cancers decreased to a far lesser extent (58.6 cases per 100,000 women before screening to 51.8 cases per 100,000 women after implementation of screening, incidence rate ratio 0.88, 0.81 to 0.97, P<0.001)., Conclusions: The extension of the upper age limit to 75 years has only led to a small decrease in incidence of advanced stage breast cancer, while that of early stage tumours has strongly increased., (© de Glas et al 2014.)

Background: Neoadjuvant hormonal therapy (NHT) is playing an increasing role in the clinical management of breast cancer (BC) and may improve surgical outcomes for postmenopausal, oestrogen receptor (ER)-positive BC patients. However, there is currently no consensus on the optimal duration of NHT before surgery. Here, we present the outcomes of the TEAM IIA trial, a multicentre, phase II trial investigating the efficacy of six months of neoadjuvant exemestane in postmenopausal, strong ER-positive (ER+, ⩾50%) BC patients., Methods: 102 patients (stage T2-T4ac) were included in the study after exclusion of ineligible patients. Primary end-point was clinical response at 3 and 6 months as measured by palpation. Secondary end-point was radiological response as measured by magnetic resonance imaging (MRI), mammography and/or ultrasound. Linear mixed models (95% confidence interval (CI)) were used to compare changes in mean tumour size (in mm) between baseline, 3 and 6 months after the start of endocrine therapy. Conversion rates from mastectomy to breast conserving surgery (BCS) were evaluated., Results: Median age of all patients was 72 years (range 53-88). Overall response rate by clinical palpation was 64.5% in all patients with a final palpation measurement. Four patients had clinically progressive disease. 63 patients had both 3-month and >3-month palpation measurements. Overall response was 58.7% at 3 months and 68.3% at final palpation (>3 months). Mean tumour size by clinical palpation at T=0 was 39.1mm (95% CI 34.8-43.4mm), and decreased to 23.0mm (95% CI 18.7-27.2mm) and 16.7 mm (95% CI 12.6-20.8) at T=3 and T>3 months, respectively (p=0.001). Final radiological response rates at the end of treatment for MRI (n=37), ultrasound (n=77) and mammography (n=56) were 70.3%, 41.6% and 48.2%, respectively. Feasibility of BCS improved from 61.8% to 70.6% (McNemar p=0.012)., Conclusion: 6 months of neoadjuvant exemestane therapy helps reduce mean tumour size further in strongly ER-positive BC patients without significant side-effects compared to 3 months. Nevertheless, some patients still experience disease progression under exemestane. Feasibility of breast conservation rates improved by almost 10%., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Treatment decisions in early breast cancer can revolve around type of surgery and whether or not to have adjuvant systemic therapy. This systematic review aims to give an overview of patient self-reported factors affecting preferences for breast conserving surgery (BCS) versus mastectomy (MAST), the minimal benefit patients require from adjuvant chemotherapy (aCT) and/or adjuvant hormonal therapy (aHT) to consider it worthwhile, and factors influencing this minimally-required benefit., Methods: PubMed and EMBASE were searched for relevant articles. Two reviewers independently selected articles and extracted data., Results: We identified 15 studies on surgical and six on adjuvant systemic treatment decision-making. Factors affecting patient preference for BCS most frequently related to body image (44%), while factors influencing preference for MAST most often related to survival/recurrence (46%). To make adjuvant systemic therapy worthwhile, the median required absolute increase in survival rate was 0.1-10% and the median required additional life expectancy was 1 day to 5 years. The range of individual preferences was wide within studies. Participants in the aHT studies required larger median benefits than those in the aCT studies. Factors associated with judging smaller benefits sufficient most often (44%) related to quality of life (e.g., less treatment toxicity)., Conclusion: Decisive factors in patients' preferences for surgery type commonly relate to body image and survival/recurrence. Most participants judged small to moderate benefits sufficient to consider adjuvant systemic therapy worthwhile, but individual preferences varied widely. Clinicians should therefore consider the patient's preferences to tailor their treatment recommendations accordingly., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Breast cancer is a heterogeneous disease with a highly variable clinical outcome in which both genetic and epigenetic changes have critical roles. We investigated tumor expression levels of histone-modifying enzymes LSD1, HDAC2 and SIRT1 in relation with patient survival and tumor relapse in a retrospective cohort of 460 breast cancer patients. Additionally, we correlated expression levels with tumor differentiation and tumor cell proliferation., Methods: Immunohistochemical staining for LSD1, HDAC2 and SIRT1 was performed on tissue microarrays of tumor and corresponding normal formalin-fixed paraffin-embedded tissues from breast cancer patients. Median nuclear expression levels in tumor tissues were used to divide the patients into low and high expression categories. In combined expression analyses, patients were divided into four subgroups: 1, all enzymes below-median; 2, one enzyme above-median; 3, two enzymes above-median; 4, all three enzymes above-median. The Cox proportional hazard model was used for univariate and multivariate survival analyses. The Pearson Chi-square method was used to assess correlation of combined expression levels with tumor cell proliferation and tumor differentiation., Results: Expression of LSD1 and SIRT1, but not of HDAC2, was significantly increased in tumor tissues compared to their normal counterparts (both p < 0.001). Multivariate survival analyses identified SIRT1 as independent prognostic factor for relapse-free survival (RFS) with a hazard ratio (HR) of 1.34 (95% CI = 1.04-1.74, p = 0.02). For overall survival (OS), no significant differences were found when the individual enzymes were analyzed. Analyses of combined expression levels of the three histone-modifying enzymes correlated with OS (p = 0.03) and RFS (p = 0.006) with a HR of respectively 1.49 (95% CI = 1.07-2.08) and 1.68 (95% CI = 1.16-2.44) in multivariate analyses and were also related to tumor differentiation (p < 0.001) and tumor cell proliferation (p = 0.002)., Conclusions: When the combined expression levels were analyzed, high expression of LSD1, HDAC2 and SIRT1 showed shorter patient survival time and shorter time to tumor relapse and correlated with poor tumor differentiation and a high level of tumor cell proliferation. Expression of these histone-modifying enzymes might therefore be involved in breast cancer pathogenesis.

With the ongoing ageing of western societies, the proportion of older breast cancer patients will increase. For several years, clinicians and researchers in geriatric oncology have urged for new clinical trials that address patient-related endpoints such as functional decline after treatment of older patients. The aim of this study was to present an overview of trial characteristics and endpoints of all currently running clinical trials in breast cancer, particularly in older patients. The clinical trial register of the United States National Institutes of Health Differences was searched for all current clinical trials on breast cancer treatment. Trial characteristics and endpoints were retrieved from the register and differences in characteristics between studies in older patients specifically (defined as a lower age-limit of 60 years or older) and trials in all patients were assessed using χ(2) tests. We included 463 clinical trials. Nine trials (2 %) specifically investigated breast cancer treatment in older patients. Ninety-one breast cancer trials included any patient-related endpoint (20 %), while five trials specifically addressing older patients included any patient-related endpoint (56 %, P = 0.02). Five of the trials in older patients incorporated a geriatric assessment (56 %). Clinical trials still rarely incorporate patient-related endpoints, even in trials that specifically address older patients. Trials that are specifically designed for older patients do not often incorporate a geriatric assessment in their design. This implicates that current clinical studies are not expected to fill the gap in knowledge concerning treatment of older breast cancer patients in the next decade.

Background: Classical patient and tumour characteristics are the benchmark of personalised breast cancer (BC) management. Recent evidence has demonstrated that immune and molecular profiling of BC may also play an important role. Despite evidence of differences between invasive ductal (IDC) and lobular (ILC) BC, they are infrequently accounted for when making treatment decisions for individual patients. The purpose of this study was to investigate the relevance of the tumour immune response in the major histological subtypes of BC. We also assessed the relationship between immune responses and molecular subtypes and their prognostic potential., Methods: Immunostains were done for HLA-I, HLA-E, HLA-G, Tregs, NK cells and CTLs for the composition of the immune profiles and Ki67, EGFR, CK5/6, ER, PR and HER2 for molecular profiles in 714 breast cancer patients who underwent primary surgery., Results: No significant association was found between IDC (90.6%) and ILC (9.4%) and tumour immune subtypes (P=0.4) and molecular subtypes (P=0.4). However, for the relapse-free period (RFP) tumour immune subtyping was prognostic (P=0.002) in IDC, but not ILC. Contrary to ILC, IDC patients frequently expressed higher cleaved caspase-3 and Ki67, which was prognostic. Intermediate immune-susceptible IDC expressing high cleaved caspase-3 or Ki67 showed worse RFP than those with low expression (caspase-3: P=0.004; Ki67: P=0.002); this was not seen for ILC or in high or low immune-susceptible tumour types for either IDC or ILC., Conclusions: Tumour immune characteristics and host immune responses are prognostic in IDC, but not ILC. In addition, tumour immune profiles are only prognostic in Luminal A tumours.

Purpose: To compare the distribution and prognostic effect of the breast cancer molecular subtypes in young and elderly breast cancer patients., Patients and Methods: Our study population (n = 822) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. A total of 142/822 fresh frozen tissues were available with good quality RNA and analyzed by gene expression microarray. Gene expression molecular subtypes were determined by correlation to the expression centroids of 534 "intrinsic" genes. Sections of a tissue micro array containing formalin-fixed paraffin-embedded tumor tissue of 714/822 patients were immunohistochemically (IHC) stained for Ki67, EGFR, CK5/6. Tumor expression of ER, PR, HER2 was previously determined. IHC molecular subtypes were defined based on expression of these markers: Luminal A: ER+ and/or PR+, HER2- and Ki67-; Luminal B: ER+ and/or PR+ and ki67+; ERBB2: ER-, PR- and HER2+; Basal-like: ER-, PR-, HER2- and EGFR+ and/or CK5/6+; Unclassified: ER-, PR-, HER2-, EGFR- and CK5/6-. IHC molecular subtypes were validated against gene expression defined molecular subtypes. Assessment of distribution and prognostic effect of molecular subtypes was stratified to age (<65 versus ≥65 years)., Results: Validation of molecular subtypes determined by IHC against gene expression revealed a substantial agreement in classification (Cohen's kappa coefficient 0.75). A statistically significant association (p = 0.02) was found between molecular subtypes and age, where Luminal tumors were more often found in elderly patients, while ERBB2, basal-like and unclassified subtypes were more often found in young patients. Molecular subtypes showed a prognostic association with outcome in young patients concerning relapse-free period (RFP) (p = 0.01) and relative survival (RS) (p < 0.001). No statistically significant prognostic effect was found for molecular subtypes in elderly patients (RFP p = 0.5; RS p = 0.1). Additional analyses showed that no molecular subtypes showed a statistically significant difference in outcome for elderly compare to young patients., Conclusion: We have shown that molecular subtypes have a different distribution and prognostic effect in elderly compared to young breast cancer patients, emphasizing the fact that biomarkers may have different distributions and prognostic effects and therefore different implications in elderly compared to their younger counterparts. Our results support the premise that breast cancer clinical behavior is significantly affected by patient age. We suggest that competing risks of death in elderly patients, ER-driven differences and micro-environmental changes in biology are underlying these age-dependent variations in patient prognosis., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)