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Background and Purpose: In this study, we conducted a population-based retrospective audit of heart doses for high-risk breast cancer (BC) over a nine-year period in patients treated with adjuvant CT-based radiotherapy in a comprehensive and homogenized national BC cohort. Additionally, this serves as a demonstration of performing large scale audits with consistent delineations created by an auto-segmentation tool., Materials and Methods: High-risk BC patients treated with adjuvant radiotherapy in the period 2008-2016 from all seven radiotherapy centres in Denmark were included. A homogenized cohort was created using an inhouse developed auto-segmentation tool. The homogenized cohort volume and planned doses (mean heart dose (MHD), V20Gy and V40Gy) were evaluated. Volumes and dose metrics were compared for clinical and homogenized heart volumes., Results: Among 6925 patients, 5589(81 %) had a clinical heart delineation. The median delineated heart volume increased from 531.9 ml (2008) to 638.5 ml (2016) (p < 0.01). The median MHD for the homogenized cohort was 1.58 Gy (2008-2016) with an overall decreasing trend, 2.14 Gy in left- and 1.08 Gy in right-sided patients. The median MHD in the clinically delineated hearts was 0.01 Gy lower than the planned median MHD in the homogenized cohort., Conclusion: During 2008-2016 the planned heart dose has been low across the population. A volume increase was observed in the clinically delineated hearts, however the median MHD in the homogenized cohort was low, with 1.58 Gy. The study demonstrated the possibilities for full population-based and consistent dose audit by using auto-segmentation tools., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose/objective: The Danish Breast Cancer Group (DBCG) IMN2 study investigated the gain from internal mammary node irradiation (IMNI) in node-positive breast cancer patients. IMNI was indicated in right-sided patients, but not in left-sided. Target volume delineations were based on bony landmarks in contrast to the contemporary vessel-based ESTRO consensus guideline. Our objective was to compare IMNI doses in right-sided versus left-sided patients., Material/methods: Treatment plans and delineated structures including CTVn&#95;IMN (IMN&#95;old) from 2008 to 2014 were collected from the DBCG RT Nation study. During the study period, IMN&#95;old was only delineated in right-sided patients. Right and left-sided CTVn&#95;IMN structures were auto-segmented following the ESTRO guidelines (IMN&#95;ESTRO). Due to cranial discordance between IMN&#95;old and IMN&#95;ESTRO, the IMN&#95;ESTRO models were separated into IMN&#95;ESTRO&#95;cranial and IMN&#95;ESTRO&#95;intercostal space(IC)1-3, IC1-4, and IC4&#95;only., Results: Treatment plans for 2837 patients were available (62.5 % of patients in the IMN2 study). In right-sided patients, the median IMN&#95;old dose coverage (92.4 %) was higher than IMN&#95;ESTRO (71.7 %), p < 0.001. Dose coverage in IMN&#95;ESTRO&#95;IC1-3 was comparable to IMN&#95;old. Comparing IMN&#95;ESTRO&#95;IC1-3 in all patients by laterality, the median CTVn&#95;V90% was 94.6 % (IQR 64.8-100.0) in right-sided patients and 20.4 % (IQR 0.9-55.8) in left-sided patients, p < 0.001. For right-sided patients, median CTV&#95;V90% was 82.3 % in IMN&#95;ESTRO&#95;IC4&#95;only. Median mean heart doses were lower in right-sided patients (1.2 Gy) than in left-sided (2.3 Gy), p < 0.001. Median mean lung doses were higher in right-sided patients (16.0 Gy) than in left-sided (12.7 Gy), p < 0.001., Conclusion: For IMN&#95;ESTRO&#95;IC1-3, we found a significantly higher IMN dose coverage in right-sided than in left-sided patients supporting treatment according to study guidelines in the DBCG IMN2 study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the association between irradiated breast volume and grade 2-3 breast induration three years after radiotherapy in the phase III Danish Breast Cancer Group HYPO trial randomizing patients ≥ 41 years to whole breast irradiation (WBI) with 40 Gy/15fr versus 50 Gy/25fr., Methods: Treatment plans were available for all Danish patients. Associations between frequency of induration and irradiated volume, age, smoking status, and boost were assessed by logistic regression. A sequential boost was given to patients < 50 years or in case of a narrow (<2 mm) resection margin., Results: RT plans from 1,333 patients were analyzed with 178 (13 %) having grade 2-3 induration. 1135 patients had only WBI. For this group, induration was correlated with irradiated breast volume for patients ≥ 65 years (n = 343, 10 %/22 % for small/large irradiated volumes, p = 0.005) but not for patients aged 50-64 years (n = 792, 11 % for both small and large volumes, p = 0.82). Smoking doubled the frequency irrespective of irradiated volume and age. All patients < 50 years (n = 156) had a boost. A volume effect was found for this group (5 %/21 % induration for small/large volume, p = 0.002). 42 patients ≥ 50 years had a boost and 14 (33 %) had grade 2-3 induration, however, with a p-value > 0.05 due to the few numbers of patients., Conclusion: A relationship between irradiated breast volume and 3-year frequency of breast induration was found for patients ≥ 65 years, whilst not for patients aged 50-64 years. Smoking doubled the risk of induration irrespective of volume and age. A dose-induration relationship was seen for boost patients < 50 years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Guideline adherence in radiotherapy is crucial for maintaining treatment quality and consistency, particularly in non-trial patient settings where most treatments occur. The study aimed to assess the impact of guideline changes on treatment planning practices and compare manual registry data accuracy with treatment planning data., Materials and Methods: This study utilised the DBCG RT Nation cohort, a collection of breast cancer radiotherapy data in Denmark, to evaluate adherence to guidelines from 2008 to 2016. The cohort included 7448 high-risk breast cancer patients. National guideline changes included, fractionation, introduction of respiratory gating, irradiation of the internal mammary lymph nodes, use of the simultaneous integrated boost technique and inclusion of the Left Anterior Descending coronary artery in delineation practice. Methods for structure name mapping, laterality detection, detection of temporal changes in population mean lung volume, and dose evaluation were presented and applied. Manually registered treatment characteristic data was obtained from the Danish Breast Cancer Database for comparison., Results: The study found immediate and consistent adherence to guideline changes across Danish radiotherapy centres. Treatment practices before guideline implementation were documented and showed a variation among centres. Discrepancies between manual registry data and actual treatment planning data were as high as 10% for some measures., Conclusion: National guideline changes could be detected in the routine treatment data, with a high degree of compliance and short implementation time. Data extracted from treatment planning data files provides a more accurate and detailed characterisation of treatments and guideline adherence than medical register data., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Purpose: Recommendations for regional radiotherapy (RT) of sentinel lymph node (SLN)-positive breast cancer are debated. We here report a RT quality assessment of the SENOMAC trial., Materials and Methods: The SENOMAC trial randomized clinically node-negative breast cancer patients with 1-2 SLN macrometastases to completion axillary lymph node dissection (cALND) or SLN biopsy only between 2015-2021. Adjuvant RT followed national guidelines. RT plans for patients included in Sweden and Denmark until June 2019 were collected (N = 1176) and compared to case report forms (CRF). Dose to level I (N = 270) and the humeral head (N = 321) was analyzed in detail., Results: CRF-data and RT plans agreed in 99.3 % (breast/chest wall) and in 96.6 % of patients (regional RT). Congruence for whether level I was an intended RT target was lower (78 %). In accordance with Danish national guidelines, level I was more often an intended target in the SLN biopsy only arm (N = 334/611, 55 %,) than in the cALND arm (N = 174/565, 31 %,). When an intended target, level I received prescribed dose to 100 % (IQR 98-100 %) of the volume. However, even when not an intended target, full dose was delivered to > 80 % of level I (IQR 75-90 %). The intentional inclusion of level I in the target volume more than doubled the dose received by ≥ 50 % of the humeral head., Conclusion: Congruence between CRF data and RT plans was excellent. Level I received a high dose coverage even when not intentionally included in the target. Including level I in target significantly increased dose to the humeral head., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Roger Olofsson Bagge has received institutional research grants from Bristol-Myers Squibb (BMS), Endomagnetics Ltd (Endomag), SkyLineDx and NeraCare GmbH, speaker honorarium from Roche, Pfizer and Pierre-Fabre, and has served on advisory boards for Amgen, BD/BARD, Bristol-Myers Squibb (BMS), Cansr.com, Merck Sharp & Dohme (MSD), Novartis, Roche and Sanofi Genzyme, and is a shareholder in SATMEG Ventures AB. Oreste Davide Gentilini has received honoraria for consultation, lectures and advisory roles from MSD, Astra-Zeneca, BD, Bayer, Eli-Lilly. None of the other authors declare any conflict of interest.]., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: The Danish Breast Cancer Group Internal Mammary Node study demonstrated improved 8-year overall survival (OS) with internal mammary node irradiation (IMNI) in patients with node-positive early breast cancer. Here, we present long-term results from the Danish Breast Cancer Group Internal Mammary Node study cohort., Patients and Methods: This nationwide, prospective cohort study allocated patients with node-positive early breast cancer to adjuvant radiotherapy with or without IMNI depending on cancer laterality. Patients with right-sided cancer received IMNI. Patients with left-sided cancer were treated without IMNI because of risk of radiation-induced heart disease. Other treatment was independent of laterality. The primary study end point was OS. Secondary end points were distant recurrence and breast cancer mortality. Analyses were by intention to treat., Results: During 2003-2007, 3,089 women were allocated to IMNI (right-sided, n = 1,491) or no IMNI (left-sided, n = 1,598). With a median follow-up of 14.8 years, 589 patients with and 701 patients without IMNI had died. The corresponding 15-year OS rates were 60.1% and 55.4%. The adjusted hazard ratio (HR) for death was 0.86 (95% CI, 0.77 to 0.96; P = .007) in favor of IMNI. The 15-year risk of developing distant recurrence was 35.6% (523 recurrences) and 38.6% (602 recurrences) with vs. without IMNI (adjusted HR, 0.88 [95% CI, 0.79 to 0.99; P = .04]). The 15-year breast cancer mortality with IMNI was 31.7% (467 deaths) compared with 33.9% (537 deaths) without IMNI (adjusted HR, 0.88 [95% CI, 0.78 to 1.00; P = .05]). The distribution of other deaths was similar across groups., Conclusion: In patients with node-positive early breast cancer treated with IMNI or without IMNI depending on breast cancer laterality, IMNI reduced the risk of distant recurrence and death from breast cancer, thereby improving long-term survival.

Purpose: On the basis of low risk of local recurrence in elderly patients with breast cancer after conservative surgery followed by whole breast irradiation (WBI), the Danish Breast Cancer Group initiated the noninferiority external-beam partial breast irradiation (PBI) trial (ClinicalTrials.gov identifier: NCT00892814). We hypothesized that PBI was noninferior to WBI regarding breast induration., Methods: Patients operated with breast conservation for relatively low-risk breast cancer were randomly assigned to WBI versus PBI, and all had 40 Gy/15 fractions. The primary end point was 3-year grade 2-3 breast induration., Results: In total, 865 evaluable patients (434 WBI and 431 PBI) were enrolled between 2009 and 2016. Median follow-up was 5.0 years (morbidity) and 7.6 years (locoregional recurrence). The 3-year rate of induration was 9.7% for WBI and 5.1% for PBI ( P = .014). Large breast size was significantly associated with induration with a 3-year incidence of 13% (WBI) and 6% (PBI) for large-breasted patients versus 6% (WBI) and 5% (PBI) for small-breasted patients. PBI showed no increased risk of dyspigmentation, telangiectasia, edema, or pain, and patient satisfaction was high. Letrozole and smoking did not increase the risk of radiation-associated morbidity. Sixteen patients had a locoregional recurrence (six WBI and 10 PBI; P = .28), 20 patients had a contralateral breast cancer, and eight patients had distant failure (five WBI and three PBI). A nonbreast second cancer was detected in 73 patients (8.4%), and there was no difference between groups., Conclusion: External-beam PBI for patients with low-risk breast cancer was noninferior to WBI in terms of breast induration. Large breast size was a risk factor for radiation-associated induration. Few recurrences were detected and unrelated to PBI.

Purpose: The relation between breast induration grade 2-3 at 3 years after radiation therapy and irradiated breast volume was investigated for patients in the Danish Breast Cancer Group (DBCG) Partial Breast Irradiation (PBI) trial. METHODS Treatment plan data was obtained from the Danish radiotherapy plan database. Dosimetric parameters for breast and organs at risk were determined. Breast induration data was obtained from the DBCG database. The volume of the whole breast (CTVp&#95;breast) treated to various dose levels was determined for treatment plans in both arms. Logistic regression was used to assess the frequency of induration on breast volume irradiated to ≥40 Gy. RESULTS PBI and WBI was given to 433 and 432 patients, respectively. Median and interquartile ranges (IQR) for CTVp&#95;breast were 710 mL (467-963 mL; PBI) and 666 mL (443-1012 mL; WBI) (p = 0.98). Median and IQR for CTVp&#95;breast treated to ≥40 Gy was 24.9% (18.6-32.6%; PBI) and 59.8% (53.6-68.5%; WBI). Grade 2-3 induration was observed in 5% (PBI) and 10% (WBI) of the patients. A dose-response relationship was established between irradiated breast volume and frequency of breast induration. From the model, 5% and 10% risks of breast induration were observed for ≥40 Gy delivered to CTVp&#95;breast volumes of 177 mL (95%CI, 94-260 mL) and 426 mL (95%CI, 286-567 mL), respectively. CONCLUSION The frequency of breast induration increased significantly with increasing irradiated breast volume, strongly favouring small volumes and PBI. Thus, treated breast volume - not the breast size itself - is the risk factor for induration. This is the first report directly linking the 40 Gy irradiated breast volume to breast induration., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Radiotherapy for breast cancer can increase the risks of heart disease. Patient-specific risk assessment may be improved with the inclusion of doses to cardiac substructures. The purpose of this work was to use automatic segmentation to evaluate substructure doses and develop predictive models for these based on the dose to the whole heart., Material and Methods: Automatic segmentation was used to delineate cardiac substructures in a Danish breast cancer trial (DBCG HYPO) dataset comprising over 1500 Danish women treated between 2009 and 2014. Trends in contouring practices and cardiac doses over time were investigated, and models to predict substructure doses from whole heart dose parameters were fit to the data., Results: Manual contouring consistency improved over the study period when compared with automatic segmentation; systematic differences between automatically and manually defined heart volume decreased from 106 cm 3 to 12.0 cm 3 . Doses to the heart and cardiac substructures also decreased. Mean whole heart doses for left-sided treatments in 2009 and 2014 were 1.94±1.19 Gy and 1.29±0.69 Gy (average ± SD), respectively. Prediction of mean substructure doses is accurate, with R 2 scores in the range 0.45-0.95 (average 0.77), depending on the particular structure., Conclusion: This study reports heart and cardiac substructure doses in a large breast cancer cohort. Predictive models generated in this work can be used to estimate mean cardiac substructure doses for datasets where patient imaging and dose distributions are not available, provided the tangential field techniques are consistent with those used in the trial., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Body weight and body composition may change during and after adjuvant or neo-adjuvant chemotherapy for breast cancer. However, most studies did not include a comparison group of women without cancer, thus could not assess whether observed changes differed from age-related fluctuations in body weight and body composition over time. We assessed changes in body composition during and after chemotherapy in breast cancer patients compared with age-matched women not diagnosed with cancer., Methods: We recruited 181 patients with stage I-IIIb breast cancer and 180 women without cancer. In patients, we assessed body composition using a dual-energy X-ray scan before start of chemotherapy (T1), shortly after chemotherapy (T2), and 6 months after chemotherapy (T3); for the comparison group, the corresponding time points were recruitment (T1) and 6 (T2) and 12 (T3) months., Results: Fifteen percent of patients and 8% of the comparison group gained at least 5% in body weight between T1 and T3. Among the comparison group, no statistically significant changes in body weight, or body composition were observed over time. Body weight of patients significantly increased from baseline (72.1 kg ± 0.4 kg) to T2 (73.3 kg ± 0.4 kg), but decreased to 73.0 kg ± 0.4 kg after chemotherapy (T3). Lean mass of patients significantly increased from 43.1 kg ± 0.5 kg at baseline to 44.0 kg ± 0.5 kg at T2, but returned to 43.1 kg ± 0.5 kg at T3. There were no differential changes in fat mass over time between patients and the comparison group., Conclusions: Changes in body weight and body composition during and after chemotherapy for early stage breast cancer were modest, and did not differ substantially from changes in body weight and body composition among women without cancer.

Purpose: Dutch Health care professionals (HCPs) provide little information concerning health risks associated with weight gain during chemotherapy for breast cancer. Women with breast cancer have specified the need for more information on nutrition and physical activity to deal with weight gain. The aims of this study were to assess the perceptions of Dutch HCPs on weight gain during chemotherapy and in addition evaluate whether and what kind of information on dietary intake and physical activity HCPs provide to prevent/treat weight gain during (neo)adjuvant chemotherapy., Methods: A qualitative study was conducted using semi-structured interviews with 34 HCPs involved in breast cancer care: general practitioners, oncologists, specialized nurses, and dieticians., Results: To date, little information about nutrition, physical activity, and weight gain is given during chemotherapy because it is not part of most HCPs' training, it is not included in the guidelines and it is not the best time to bring up information in the opinion of HCPs. Weight gain was perceived as just a matter of a few kilos and not an important health issue during treatment. All HCPs felt it is better that women themselves addressed their weight gain after chemotherapy., Conclusion: More knowledge about health risks associated with chemotherapy-induced weight gain and how to combat these issues needs to be made readily available to the HCPs and should become part of their training. Existing patient guidelines should include information on how to prevent and/or reduce weight gain through self-management of nutrition intake and physical activity during and post chemotherapy.

Background: More than 60% of women diagnosed with early stage breast cancer receive (neo)adjuvant chemotherapy. Breast cancer patients receiving chemotherapy often experience symptoms such as nausea, vomiting and loss of appetite that potentially affect body weight and body composition. Changes in body weight and body composition may detrimentally affect their quality of life, and could potentially increase the risk of disease recurrence, cardiovascular disease and diabetes. To date, from existing single method (quantitative or qualitative) studies is not clear whether changes in body weight and body composition in breast cancer patients are treatment related because previous studies have not included a control group of women without breast cancer., Methods: We therefore developed the COBRA-study (Change Of Body composition in BReast cancer: All-in Assessment-study) to assess changes in body weight, body composition and related lifestyle factors such as changes in physical activity, dietary intake and other behaviours. Important and unique features of the COBRA-study is that it used I) a "Mixed Methods Design", in order to quantitatively assess changes in body weight, body composition and lifestyle factors and, to qualitatively assess how perceptions of women may have influenced these measured changes pre-, during and post-chemotherapy, and II) a control group of non-cancer women for comparison. Descriptive statistics on individual quantitative data were combined with results from a thematic analysis on the interviews- and focus group data to understand patients' experiences before, during and after chemotherapy., Discussion: The findings of our mixed methods study, on chemotherapy treated cancer patients and a comparison group, can enable healthcare researchers and professionals to develop tailored intervention schemes to help breast cancer patients prevent or handle the physical and mental changes they experience as a result of their chemotherapy. This will ultimately improve their quality of life and could potentially reduce their risk for other co-morbidity health issues such as cardiovascular disease and diabetes.

Purpose: The purpose of the study was to assess self-reported taste and smell perception after chemotherapy in breast cancer patients compared with women without cancer, and to assess whether taste and smell perception is associated with quality of life after the end of chemotherapy., Methods: We included 135 newly diagnosed breast cancer patients who completed chemotherapy and 114 women without cancer. Questionnaires on taste, smell, and quality of life were completed shortly after and 6 months after chemotherapy (patients) or at two moments with 6 months' time window in between (comparisons)., Results: Self-reported taste and smell perception were significantly lower in patients shortly after chemotherapy compared to the comparison group. Most patients recovered 6 months after chemotherapy, although patients who were still receiving trastuzumab then reported a lower taste and smell perception compared to patients who were not. A lower self-reported taste and smell were statistically significantly associated with a worse quality of life, social, emotional, and role functioning shortly after chemotherapy. Six months after chemotherapy, taste and smell were statistically significantly associated with quality of life, social and role functioning, but only in patients receiving trastuzumab., Conclusions: Most taste and smell alterations recovered within 6 months after the end of chemotherapy for breast cancer, but not for patients receiving trastuzumab. These results highlight the importance of monitoring taste and smell alterations during and after treatment with chemotherapy and trastuzumab, as they may impact quality of life.

Introduction: The current study evaluates the data quality achievable using a national data bank for reporting radiotherapy parameters relative to the classical manual reporting method of selected parameters., Methods: The data comparison is based on 1522 Danish patients of the DBCG hypo trial with data stored in the Danish national radiotherapy data bank. In line with standard DBCG trial practice selected parameters were also reported manually to the DBCG database. Categorical variables are compared using contingency tables, and comparison of continuous parameters is presented in scatter plots., Results: For categorical variables 25 differences between the data bank and manual values were located. Of these 23 were related to mistakes in the manual reported value whilst the remaining two were a wrong classification in the data bank. The wrong classification in the data bank was related to lack of dose information, since the two patients had been treated with an electron boost based on a manual calculation, thus data was not exported to the data bank, and this was not detected prior to comparison with the manual data. For a few database fields in the manual data an ambiguity of the parameter definition of the specific field is seen in the data. This was not the case for the data bank, which extract all data consistently., Conclusions: In terms of data quality the data bank is superior to manually reported values. However, there is a need to allocate resources for checking the validity of the available data as well as ensuring that all relevant data is present. The data bank contains more detailed information, and thus facilitates research related to the actual dose distribution in the patients.

Background and Objectives: Breast conserving surgery (BCS) can be challenging for large regions of ductal carcinoma in situ (DCIS), resulting in high rates of positive resection margins. Radioactive seed localization (RSL) using multiple radioactive iodine ( 125 I) seeds can be used to bracket extensive DCIS (eDCIS). The goal of this study was to retrospectively compare the use of a single or multiple 125 I seeds in RSL to enable BCS in patients with eDCIS., Methods: All patients with eDCIS (area of ≥3.0 cm) who underwent either single or multiple-seed RSL between January 2008 and December 2016 were included. Patient, tumor and surgery characteristics were compared between both groups. Primary outcome measures were positive resection margin and re-operation rates., Results: Respectively 48 and 58 patients with eDCIS underwent single- and multiple-seed RSL and subsequent BCS. The rate of positive resection margin (focal and more than focal) with single-seed RSL was 47.9%, compared to 29.3% with multiple-seed RSL (p = 0.06). The re-operation rate was 39.6% with single-seed RSL and 20.7% in the multiple-seed RSL group (p = 0.05)., Conclusion: Multiple-seed RSL enables bracketing of large areas of DCIS, with the potential to decrease the high rate of positive resection margins in this patient group., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Breast cancer patients receiving chemotherapy often experience symptoms such as nausea, vomiting and loss of appetite that potentially affect dietary habits. This study assessed the intake of energy, macronutrients and food groups before and during chemotherapy in breast cancer patients compared with women without cancer, and determined the association between symptoms and energy and macronutrient intake., Methods: This study included 117 newly diagnosed breast cancer patients scheduled for chemotherapy and 88 women without cancer. Habitual intake before chemotherapy was assessed with a food frequency questionnaire. Two 24-h dietary recalls were completed on random days for each participant during the whole chemotherapy treatment for patients and within 6 months after recruitment for women without cancer. Shortly, after the dietary recall, participants filled out questionnaires on symptoms., Results: Before chemotherapy, habitual energy and macronutrient intake was similar for breast cancer patients and women without cancer. During chemotherapy, breast cancer patients reported a significantly lower total energy, fat, protein and alcohol intake than women without cancer, as shown by a lower intake of pastry and biscuits, cheese, legumes and meat products. A decline in subjective taste perception, appetite and hunger and experiencing a dry mouth, difficulty chewing, lack of energy and nausea were associated with a lower energy intake., Conclusions: Symptoms induced by chemotherapy are associated with lower dietary intake and manifested by a lower intake of specific food groups. To ensure an optimal dietary intake during chemotherapy, it is important to monitor nutritional status and symptom burden during chemotherapy in breast cancer patients.

Background and Purpose: To report on a Quality assessment (QA) of Skagen Trial 1, exploring hypofractionation for breast cancer patients with indication for regional nodal radiotherapy., Material and Methods: Deviations from protocol regarding target volume delineations and dose parameters (Dmin, Dmax, D98%, D95% and D2%) from randomly selected dose plans were assessed. Target volume delineation according to ESTRO guidelines was obtained through atlas based automated segmentation and centrally approved as gold standard (GS). Dice similarity scores (DSC) with original delineations were measured. Dose parameters measured in the two delineations were reported to assess their dosimetric outcome., Results: Assessment included 88 plans from 12 centres in 4 countries. DSC showed high agreement in contouring, 99% and 96% of the patients had a complete delineation of target volumes and organs at risk. No deviations in the dosimetric outcome were found in 76% of the patients, 82% and 95% of the patients had successful coverage of breast/chestwall and CTVn&#95;L2-4-interpectoral. Dosimetric outcomes of original delineation and GS were comparable., Conclusions: QA showed high protocol compliance and adequate dose coverage in most patients. Inter-observer variability in contouring was low. Dose parameters were in harmony with protocol regardless original or GS segmentation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Weight gain during chemotherapy in women with breast cancer is commonly reported. However, there are important differences between studies that examined weight change during chemotherapy; e.g. type of chemotherapy, menopausal status, time between body weight measurements and sample size. The purpose of this meta-analysis was to quantify changes in body weight during chemotherapy for women with breast cancer, taking these differences into account., Methods: We identified relevant studies using PubMed, Scopus and Embase databases. The search was limited to human studies published in English up to and including December 2015. Only studies among women with early stage breast cancer treated with chemotherapy, with reported body weight before and after chemotherapy and type of chemotherapy were included. Random-effect models were used, and heterogeneity between studies was explored through stratified analyses and meta-regression. Sensitivity analyses were done to explore whether a specific study markedly affected the results., Results: In total 25 papers were found, including data from 2620 women. Overall, body weight increased during chemotherapy: 2.7 kg (95% CI 2.0, 7.5) with a high degree of heterogeneity (I 2  = 94.2%). Stratified analyses showed weight gain in all strata, but did not substantially reduce heterogeneity. Univariate meta-regression showed less weight gain in prospective studies compared to chart review studies (-2.0, 95% CI: -3.1, -0.8). Studies including cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimes showed a greater weight gain compared to those that did not (2.2, 95% CI: 1.1, 3.3); and papers published until the year 2000 showed a greater weight gain compared to those published after 2000 (1.9, 95% CI:-0.8, 3.1). In the multivariate models only studies including CMF regimes and studies published until 2000 were associated with significant weight gain of respectively 1.3 and 1.4 kg., Conclusion: Despite the high heterogeneity, this meta-analysis shows significant weight gain during chemotherapy for women with breast cancer. Weight gain was more pronounced in papers published until 2000 and women receiving CMF as chemotherapy regime. Although weight gain after chemotherapy has decreased over the course of time, weight gain is still substantial and deserves clinical attention.

Background and Purpose: To internally and externally validate an atlas based automated segmentation (ABAS) in loco-regional radiation therapy of breast cancer., Materials and Methods: Structures of 60 patients delineated according to the ESTRO consensus guideline were included in four categorized multi-atlas libraries using MIM Maestro™ software. These libraries were used for auto-segmentation in two different patient groups (50 patients from the local institution and 40 patients from other institutions). Dice Similarity Coefficient, Average Hausdorff Distance, difference in volume and time were computed to compare ABAS before and after correction against a gold standard manual segmentation (MS)., Results: ABAS reduced the time of MS before and after correction by 93% and 32%, respectively. ABAS showed high agreement for lung, heart, breast and humeral head, moderate agreement for chest wall and axillary nodal levels and poor agreement for interpectoral, internal mammary nodal regions and LADCA. Correcting ABAS significantly improved all the results. External validation of ABAS showed comparable results., Conclusions: ABAS is a clinically useful tool for segmenting structures in breast cancer loco-regional radiation therapy in a multi-institutional setting. However, manual correction of some structures is important before clinical use. The ABAS is now available for routine clinical use in Danish patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer., Patients and Methods: In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat., Results: A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease., Conclusion: In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer., (© 2015 by American Society of Clinical Oncology.)

Targeting the estrogen pathway has been proven effective in the treatment for estrogen receptor positive breast cancer. There are currently two common groups of anti-estrogenic compounds used in the clinic; Selective Estrogen Receptor Modulators (SERMs, e.g. tamoxifen) and Selective Estrogen Enzyme Modulators (SEEMs e.g. letrozole). Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which make them potential candidates in hormonal treatment of breast cancer. Here we used a co-culture model in which we previously demonstrated that primary human breast adipose fibroblasts (BAFs) can convert testosterone to estradiol, which subsequently results in estrogen receptor-mediated breast cancer T47D cell proliferation. In the presence of testosterone in this model, we examined the effect of letrozole, resveratrol and melatonin on cell proliferation, estradiol (E2) production and gene expression of CYP19A1, pS2 and Ki-67. Both melatonin and resveratrol were found to be aromatase inhibitors in this co-culture system, albeit at different concentrations. Our co-culture model did not provide any indications that melatonin is also a selective estrogen receptor modulator. In the T47D-BAF co-culture, a melatonin concentration of 20 nM and resveratrol concentration of 20 μM have an aromatase inhibitory effect as potent as 20 nM letrozole, which is a clinically used anti-aromatase drug in breast cancer treatment. The SEEM mechanism of action of especially melatonin clearly offers potential advantages for breast cancer treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines are bioactive, but limited by disease burden and immune tolerance. Cyclophosphamide augments vaccine activity in tolerant neu mice and in patients with metastatic breast cancer. HER2-specific monoclonal antibodies (mAb) enhance vaccine activity in neu mice. We hypothesized that cyclophosphamide-modulated vaccination with HER2-specific mAb safely induces relevant HER2-specific immunity in neu mice and patients with HER2+ metastatic breast cancer. Adding both cyclophosphamide and the HER2-specific mAb 7.16.4 to vaccination maximized HER2-specific CD8+ T-cell immunity and tumor-free survival in neu transgenic mice. We, therefore, conducted a single-arm feasibility study of cyclophosphamide, an allogeneic HER2+ GM-CSF-secreting breast tumor vaccine, and weekly trastuzumab in 20 patients with HER2+ metastatic breast cancer. Primary clinical trial objectives were safety and clinical benefit, in which clinical benefit represents complete response + partial response + stable disease. Secondary study objectives were to assess HER2-specific T-cell responses by delayed type hypersensitivity (DTH) and intracellular cytokine staining. Patients received three monthly vaccinations, with a boost 6 to 8 months from trial entry. This combination immunotherapy was safe, with clinical benefit rates at 6 months and 1 year of 55% [95% confidence interval (CI), 32%-77%; P = 0.013] and 40% (95% CI, 19%-64%), respectively. Median progression-free survival and overall survival durations were 7 months (95% CI, 4-16) and 42 months (95% CI, 22-70), respectively. Increased HER2-specific DTH developed in 7 of 20 patients [of whom 4 had clinical benefit (95% CI, 18-90)], with a trend toward longer progression-free survival and overall survival in DTH responders. Polyfunctional HER2-specific CD8+ T cells progressively expanded across vaccination cycles. Further investigation of cyclophosphamide-modulated vaccination with trastuzumab is warranted., (©2014 American Association for Cancer Research.)

Background: The DBCG-IMN is a nationwide population-based cohort study on the effect of internal mammary node radiotherapy (IMN-RT) in patients with node positive early breast cancer. Due to the risk of RT-induced heart disease, only patients with right-sided breast cancer received IMN-RT, whereas patients with left-sided breast cancer did not. At seven-year median follow-up, a 3% gain in overall survival with IMN-RT has been reported. This study estimates IMN doses and doses to organs at risk (OAR) in patients from the DBCG-IMN. Numbers needed to harm (NNH) if patients with left-sided breast cancer had received IMN-RT are compared to the number needed to treat (NNT)., Material and Methods: Ten percent of CT-guided treatment plans from the DBCG-IMN patients were selected randomly. IMNs and OAR were contoured in 68 planning CT scans. Dose distributions were re-calculated. IMNs and OAR dose estimates were compared in right-sided versus left-sided breast cancer patients. In six left-sided patients, IMN-RT was simulated, and OAR doses were compared to those in the original plan. The NNH resulting from the change in mean heart dose (MHD) was calculated using a published model for risk of RT-related ischemic heart death., Results: In original plans, the absolute difference between right- and left-sided V90% to the IMNs was 38.0% [95% confidence interval (5.5%; 70.5%), p < 0.05]. Heart doses were higher in left-sided plans. With IMN-RT simulation without regard to OAR constraints, MHD increased 4.8 Gy (0.9 Gy; 8.7 Gy), p < 0.05. Resulting NNHs from ischemic heart death were consistently larger than the NNT with IMN-RT., Conclusion: Refraining from IMN-RT on the left side may have spared some ischemic heart deaths. Assuming left-sided patients benefit as much from IMN-RT as right-sided patients, the benefits from IMN-RT outweigh the costs in terms of ischemic heart death.

Background: Recently, two case-control studies showed that vasomotor menopausal symptoms (VMS), i.e. hot flushes (HF) and night sweats (NS), are associated with a decreased risk of breast cancer. Until now, however, no prior studies have prospectively examined the association between VMS and breast cancer incidence. We investigated this in a population-based cohort of mid-aged women in Australia., Methods: We included 11,297 women without a history of breast cancer aged 47-52 years from the Australian Longitudinal Study on Women's Health, surveyed every 3 years from 1998 to 2010. Information regarding first invasive breast cancer events and date of diagnosis was obtained from cancer registries. We determined the association between HF and NS and breast cancer occurrence before the subsequent survey, using time-dependent cox regression analysis, adjusting for time-varying lifestyle factors., Results: At baseline 33.1% of the women reported experiencing HF and 24.6% reported NS. During a mean follow-up of 13.7 years, 348 cases of breast cancer occurred. VMS were not associated with breast cancer; adjusted hazard ratios were 1.09; 95% confidence interval (CI) 0.87-1.35 for HF and 1.06; 95% CI 0.84-1.33 for NS. No significant interactions were found between each of body mass index, alcohol use, current hormone therapy use, menopausal status and VMS and breast cancer (p-values>0.05)., Conclusions: We did not find an association between VMS and breast cancer incidence. Research in this area is scarce and additional large prospective population-based studies are required to confirm or refute these findings., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: During the past decade planning of adjuvant radiotherapy (RT) of early breast cancer has changed from two-dimensional (2D) to 3D conformal techniques. In the planning computerised tomography (CT) scan both the targets for RT and the organs at risk (OARs) are visualised, enabling an increased focus on target dose coverage and homogeneity with only minimal dose to the OARs. To ensure uniform RT in the national prospective trials of the Danish Breast Cancer Cooperative Group (DBCG), a national consensus for the delineation of clinical target volumes (CTVs) and OARs was required., Material and Methods: A CT scan of a breast cancer patient after surgical breast conservation and axillary lymph node (LN) dissection was used for delineation. During multiple dummy-runs seven experienced radiation oncologists contoured all CTVs and OARs of interest in adjuvant breast RT. Two meetings were held in the DBCG Radiotherapy Committee to discuss the contouring and to approve a final consensus. The Dice similarity coefficient (DSC) was used to evaluate the delineation agreement before and after the consensus., Results: The consensus delineations of CTVs and OARs are available online and a table is presented with a contouring description of the individual volumes. The consensus provides recommendations for target delineation in a standard patient both in case of breast conservation or mastectomy. Before the consensus, the average value of the DSC was modest for most volumes, but high for the breast CTV and the heart. After the consensus, the DSC increased for all volumes., Conclusion: The DBCG has provided the first national guidelines and a contouring atlas of CTVs and OARs definition for RT of early breast cancer. The DSC is a useful tool in quantifying the effect of the introduction of guidelines indicating improved inter-delineator agreement. This consensus will be used by the DBCG in our prospective trials.

Objective: Adjuvant hormonal therapy using tamoxifen or aromatase inhibitors result in menopausal symptoms. Non-prescription dietary supplements containing plant-based phytoestrogens are often used to relieve menopausal symptoms. Phytoestrogens may reduce the action of tamoxifen and aromatase inhibitors. The purpose of this study is to gain insight into the potential risks of phytoestrogen supplementation during adjuvant hormonal therapy for breast cancer using tamoxifen or aromatase inhibitors., Design: Literature survey., Method: We performed a PubMed search for articles about studies on the effects of phytoestrogens on breast cancer treatment efficacy. We also searched on the basis of references in the articles we found in PubMed., Results: Studies based on in-vitro models as well as experimental animal models were identified. The studies on the interaction between phytoestrogen and tamoxifen showed contradictory results. The few studies pertaining to the interactive effect of phytoestrogens on aromatase inhibitors all showed a reduction in therapeutic efficacy of aromatase inhibitors caused by phytoestrogens., Conclusion: The outcomes of the studies we found suggest that caution should be exercised when taking phytoestrogen in combination with either tamoxifen or aromatase inhibitors. We believe that patients with breast cancer should be informed of this as a matter of routine.

In breast cancer, the interaction between estrogen-producing breast adipose fibroblasts (BAFs) and estrogen-dependent epithelial tumor cells is pivotal. Local estrogen production is catalyzed by aromatase, which is differentially regulated in disease-free and tumorigenic breast tissue. The use of aromatase inhibitors to block local estrogen production has proven effective in treatment of estrogen-dependent breast cancer. However, a major problem during breast cancer treatment is the sudden onset of menopause and many women seek for alternative medicines, such as the soy isoflavone genistein. In this study, we show that genistein can induce estrogen-dependent MCF-7 tumor cell growth and increase breast cancer-associated aromatase expression and activity in vitro. We have previously developed an in vitro breast cancer model where the positive feedback loop between primary BAFs and estrogen-dependent MCF-7 tumor cells is operational, thereby representing a more natural in vitro model for breast cancer. In this model, genistein could negate the growth inhibitory action of the aromatase inhibitor fadrozole at physiologically relevant concentrations. These data suggest that soy-based supplements might affect the efficacy of breast cancer treatment with aromatase inhibitors. Considering the high number of breast cancer patients using soy supplements to treat menopausal symptoms, the increasing risk for adverse interactions with breast cancer treatment is of major concern and should be considered with care., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In our present study, 12 new cis-stilbene derivatives (CRI-1-CRI-13) related to VIOXX((R)) were synthesized and studied for their inhibitory effects on cell cycle progression and anti-estrogenicity in human adenoma breast cancer MCF-7 cells. Based on the different substituents in the cis-stilbene molecule, we studied a possible structure activity relationship (SAR) for the inhibition of the cell cycle, cytotoxicity and (anti-) estrogenicity. The results showed that some cis-stilbenes have a pronounced effect on cell cycle distribution. CRI-5, 7, 10 and 12 caused an arrest of G2/M phase and reduction of G1/S phase in all tested doses (1-50 microM). In addition, some of these cis-stilbenes, have a moderate anti-estrogenic effect around 10 microM. Based on these results a preliminary SAR for cis-stilbene derivatives is suggested in which the presence and position of methoxy or thiomethoxy groups play an essential role in this cell cycle arrest. For this substitution on the para position of the left aromatic ring appears to be a prerequisite. However, the SAR for anti-estrogenicity appears to be different, but experimental information was too limited to define a possible SAR. In conclusion, our study shows that some synthetic cis-stilbene related to VIOXX might have chemopreventive properties that can effectively interfere with the cell cycle distribution of breast tumor cells.

Objective: To compare 14-gauge SCNB (stereotactic core needle biopsy) with surgery and to investigate tissue-heterogeneity of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth-factor receptor (HER-2) for nonpalpable breast cancers. To determine the number of cores needed for assessment of these factors., Materials and Methods: Cores of 41 invasive cancers were collected in three containers: the 1st into A, the 2nd and 3rd into B and subsequent cores into C. ER, PR and HER-2 were scored by immunohistochemistry and if 2+ or 3+, by chromogenic-in-situ-hybridisation (CISH) for containers and for surgical specimen., Results: Between SCNB and surgical specimen concordance was 83% (kappa = 0.39) for ER, 88% (kappa = 0.69) for PR and HER-2 and 93% (kappa = 0.63) for HER-2 after CISH. For the most discordant cases, status was positive in cores but negative in surgery: 5/7 for ER (p = 0.459), 5/5 for PR (p = 0.063), and 4/5 for HER-2 (p = 0.375), after CISH 3/3 (p = 0.250), but the difference was not statistically significant. Concordances between containers of cores was 100% (kappa = 1), 85% (kappa = 0.66) and 85% (kappa = 0.66), respectively. With more than three cores, sensitivities of 95%, 100% and 100% were reached., Conclusions: SCNB is at least as sensitive as surgery in assessment of ER, PR and HER-2. Three cores are needed for reliable assessment of HER-2 after adding CISH and more than three cores for PR, possibly due to tissue heterogeneity. For ER sensitivity remained lower, 95%, even in multiple cores, therefore ER-negative cases should be further investigated from surgical specimens.

This paper describes the procedure of changing from 2D to 3D treatment planning guidelines for post-mastectomy radiotherapy in Denmark. The aim of introducing 3D planning for post-mastectomy radiotherapy was to optimize the target coverage and minimize the dose to the normal tissues. Initially, it was investigated whether it was possible to find a treatment technique alternative to the one recommended by the Danish Breast Cancer Cooperative Group (DBCG). A dosimetric comparison of a combined photon/electron 3-field technique (3F) and a partial wide tangent technique (PWT) was carried out on individual planning CT-scans from seven patients selected to represent a wide range of sizes and shapes of chest walls. The heart dose was lower for PWT than for 3F, however, for both techniques the dose was within the accepted constraints. The lung dose was higher but acceptable for six of the seven patients with PWT. The dose to the internal mammary nodes (IMN) was not satisfactory for five of the seven patients for 3F, whereas only two of the seven patients had a minimum dose lower than 95% of the prescribed dose with PWT. Finally, the dose to the contralateral breast was increased when using PWT compared to 3F. It was concluded that PWT was an appropriate choice of technique for future radiation treatment of post-mastectomy patients. A working group was formed and guidelines for 3D planning were developed during a series of workshops where radiation oncologists and physicists from all radiotherapy centres participated. This work also included a definition of the tissue structures needed to be outlined on the planning CT-scan. The work was initiated in 2003 and the guidelines were approved by the DBCG Radiotherapy Committee in 2006. The first of January 2007 the 3D guidelines had been fully implemented in five of the seven radiotherapy centres.

Humans are exposed to a variety of food-borne phytochemicals (PC) as well as synthetic chemicals (SC). Some of these compounds have been reported to have estrogenic or anti-estrogenic properties and are therefore suspected endocrine disruptors. Until now it remains unclear if non-additive effects occur in combinations with endogenous estrogens, such as 17beta-estradiol (E(2)). To investigate such interactions, several PC and SC were tested individually, in mixtures and as combinations of mixtures with E(2) for effects on ERalpha receptor mediated cell proliferation and estrogen regulated pS2 expression level in MCF-7(bus) cells. PCs (coumestrol, genistein, naringenin, catechin, epicatechin, quercetin) or SCs (4-nonylphenol, octylphenol, beta-hexachlorocyclohexane, bisphenol A, methoxychlor, dibutyl phthalate) were mixed (PCmix and SCmix) either in concentrations reflecting human serum concentrations or at equipotent concentrations for estrogenicity. EC(50) values were applied in two approaches of the concentration-addition model (the method of isoboles and the cumulative estrogen equivalency method) to assess mixture effects. In both models PCmix and SCmix or combinations of the mixtures with E(2) showed no departure from additivity. In conclusion, the tested PCs and SCs appeared to act as (full) agonists for the estrogen receptor and interacted in mixtures and with estradiol in an additive way. In addition, it is concluded that the possible contribution of food-borne PCs to the estrogenic effect of xenobiotics is likely to be more significant than that caused by food-borne SCs.

Optimization of radiation treatment planning requires estimations of the normal tissue complication probability (NTCP). A number of models exist that estimate NTCP from a calculated dose distribution. Since different dose calculation algorithms use different approximations the dose distributions predicted for a given treatment will in general depend on the algorithm. The purpose of this work is to test whether the optimal NTCP parameter values change significantly when the dose calculation algorithm is changed. The treatment plans for 17 breast cancer patients have retrospectively been recalculated with a collapsed cone algorithm (CC) to compare the NTCP estimates for radiation pneumonitis with those obtained from the clinically used pencil beam algorithm (PB). For the PB calculations the NTCP parameters were taken from previously published values for three different models. For the CC calculations the parameters were fitted to give the same NTCP as for the PB calculations. This paper demonstrates that significant shifts of the NTCP parameter values are observed for three models, comparable in magnitude to the uncertainties of the published parameter values. Thus, it is important to quote the applied dose calculation algorithm when reporting estimates of NTCP parameters in order to ensure correct use of the models.

In the public opinion, phytochemicals (PCs) present in the human diet are often considered beneficial (e.g. by preventing breast cancer). Two possible mechanisms that could modulate tumor growth are via interaction with the estrogen receptor (ER) and inhibition of aromatase (CYP19). Multiple in vitro studies confirmed that these compounds act estrogenic, thus potentially induce tumor growth, as well as aromatase inhibitory, thus potentially reduce tumor growth. It is thought that in the in vivo situation breast epithelial (tumor) cells communicate with surrounding connective tissue by means of cytokines, prostaglandins and estradiol forming a complex feedback mechanism. Recently our laboratory developed an in vitro co-culture model of healthy mammary fibroblasts and MCF-7 cells that (at least partly) simulated this feedback mechanism (M. Heneweer et al., TAAP vol. 202(1): 50-58, 2005). In the present study biochanin A, chrysin, naringenin, apigenin, genistein and quercetin were studied for their estrogenic properties (cell proliferation, pS2 mRNA) and aromatase inhibition in MCF-7 breast tumor cells, healthy mammary fibroblasts and their co-culture. The proliferative potency of these compounds in the MCF-7 cells derived from their EC(50)s decreased in the following order: estadiol (4*10(-3) nM)>biochanin A (9 nM)>genistein (32 nM)>testosterone (46 nM)>naringenin (287 nM)>apigenin (440 nM)>chrysin (4 microM). The potency to inhibit aromatase derived from their IC(50)s decreased in the following order: chrysin (1.5 microM)>naringenin (2.2 microM)>genistein (3.6 microM)>apigenin (4.1 microM)>biochanin A (25 microM)>quercetin (30 microM). The results of these studies show that these PCs can induce cell proliferation or inhibit aromatase in the same concentration range (1-10 microM). Results from co-cultures did not elucidate the dominant effect of these compounds. MCF-7 cell proliferation occurs at concentrations that are not uncommon in blood of individuals using food supplements. Results also indicate that estrogenicity of these PCs is quantitatively more sensitive than aromatase inhibition. It is suggested that perhaps a more cautionary approach should be taken for these PCs before taken as food supplements.

Background and Objective: Many environmental and genetic factors influence the development of chemoresistance. The goal of this study was to characterize the genetic variation in the ABCB1, GSTM1, GSTT1 and GSTP1 genes, as well as the haplotype structure in the ABCB1 gene., Methods: Variants in these genes were studied in 109 healthy controls and 93 breast cancer cases, both of Caucasian origin. The cases were analyzed in relation to TP53 mutation status and response to doxorubicin. Both single and multiple single nucleotide polymorphism analyses were performed., Results: Chi-square analyses revealed a significant association between TP53 mutation status and both the GA genotype of ABCB1 exon 11 (Ser400Asn) and the GG genotype of GSTP1 (Ile105Val; P<0.01 and P<0.05, respectively). Multifactor dimensionality reduction showed that carriers of the combined GG genotype for GSTP1 and the GG for ABCB1 exon 11 had the highest chance of acquiring a mutation in the TP53 gene (P<0.02). Haplotype analysis of ABCB1 revealed a significantly different distribution of haplotypes between the breast cancer cases and the controls (P<0.01). A specific haplotype association to TP53 mutation (P<0.01) distant metastases (P<0.05) and estrogen receptor status (P<0.05) was also observed in the case group., Conclusion: An association between polymorphisms in GSTP1 and ABCB1 and risk of acquiring intratumoral TP53 mutations suggests the existence of putative predisposing genotype backgrounds. The degree of linkage disequilibrium in the ABCB1 gene was higher in healthy individuals, whereas haplotypes in the cases seemed degenerated by a number of low frequency variants. This observation may either point to the existence of a protective haplotype in the controls or may underline the importance of the accumulation of low frequency variants as susceptibility factors.

Objective: Lesions that present with nipple discharge typically are not visible on mammography or sonography but can be detected on galactography. Therefore, the usual methods for preoperative localization (wire placement under sonography or stereotactic guidance) are not applicable. We report our preliminary experience of galactography-aided stereotactic wire (n = 8) or coil (n = 1) localization of small intraductal lesions., Conclusion: Galactography-aided wire or coil localization is a practical localization method for intraductal lesions not detectable on mammography or sonography.

Approximately 60% of all breast tumors are estrogen-responsive and chemicals that show estrogenic or anti-estrogenic properties are able to interact with breast tumor growth. In a breast tumor, adipose stromal cells (fibroblasts) surrounding the epithelial tumor contain the aromatase enzyme, which converts androgens into estrogens. Exposure to aromatase inducers can therefore lead to increased estrogen levels and possibly to accelerated breast tumor growth. Subsequently, breast tumor cells synthesize and secrete elevated levels of factors such as prostaglandin E2 (PGE2), interleukin-6 (IL-6), and IL-6 soluble receptor (IL-6sR), which in turn have the ability to stimulate aromatase gene transcription in fibroblasts, establishing a positive feedback loop. In this study, a technique that allows for culturing MCF-7 epithelial breast tumor cells and healthy primary human mammary fibroblasts together in one compartment was developed. To establish the positive feedback loop, the co-culture was exposed to estrogenic compounds. RNA was isolated and reverse-transcriptase polymerase chain reaction (RT-PCR) was performed on the aromatase and pS2 genes. Exposure of the co-culture to estradiol (E2), diethylstilbestrol (DES), and bisphenol-A (BPA), resulted in a three- to seven-fold increase of pS2 transcription levels. Furthermore, pS2 transcription levels increased even more when the aromatase substrate testosterone (20 nM) was present in the co-culture medium. Exposure of the co-culture to the aromatase inducer dexamethasone (DEX) resulted in increased pS2 transcription levels, as well as increased aromatase transcription levels. Simultaneous exposure to DEX and the synthetic anti-estrogen ICI 182,780 almost completely blocked the pS2 response. The aromatase induction response was not altered by ICI 182,780 treatment. Simultaneous exposure to DEX and the non-steroidal aromatase inhibitor fadrozole, abolished the effect of the presence of testosterone in the co-culture medium, but did not result in pS2 gene transcription levels as low as seen after exposure to ICI 182,780. These observations indicate the presence of a positive feedback loop in our co-culture system. This co-culture provides a more sophisticated and sensitive system to detect direct and indirect estrogenic effects of compounds and their possible effects on breast tumor promotion.

Aim: To determine the incidence of and reasons for recurrences after immediate breast reconstruction in breast cancer patients., Material and Methods: The data of 79 patients undergoing immediate breast reconstruction between 1998 and 2001 in Kuopio University Hospital were re-examined from both the local cancer register and the patient charts at the end of year 2003., Results: There were five local recurrences (6.3%), one regional recurrence (1.2%), and three cases (3.8%) presented bone and/or visceral metastases. All recurrences except one (primary tumor noninvasive) appeared within the first two years after primary therapy. Young age and increasing size of the tumour were risk factors for distant or logoregional metastases., Conclusion: Immediate breast reconstruction is a safe procedure in breast cancer patients, but a multidisciplinary team is needed for careful patient selection.

MHC peptides derived from tumor-associated antigens (TAAs) can serve as the basis for the development of immunotherapeutics to treat human malignancies. Previously, we identified novel HLA-A*0201 (HLA-A2)-restricted peptides recovered from soluble HLA molecules secreted by human tumor cell lines, transfected with truncated genes of HLA-A2 and HLA-B7. Here, 4 candidate peptides eluted from soluble HLA-A2 were selected on the basis of their precursor proteins being TAAs. Peptide p1028 (GLIEKNIEL), derived from DNA methyltransferase I (DNMT-1), which is overexpressed in various human tumors, showed the highest affinity to HLA-A2 and was relatively abundant in the sMHC/peptide complexes of all transfected breast, ovarian and prostate cancer cell lines. Peptide p1028-specific CTLs were generated in vitro and shown to efficiently lyse not only target cells pulsed with the peptide but also HLA-A2-positive breast cancer cell lines MDA-231 and MCF-7. The peptide induced IFN-gamma production in CTLs, which were selectively stained by a p1028 tetramer. Since DNMT-1 is a widely expressed tumor-associated enzyme, the novel DNMT-1-derived, HLA-A2-restricted peptide GLIEKNIEL identified here may provide a suitable candidate for a therapeutic cancer vaccine.

Aim: The aim of our study was to (1) examine the incidence of surgical complications, (2) determine the incidence of loco-regional recurrences and (3) examine the safety of saving the nipple-areola-complex after immediate breast reconstructions in breast cancer., Methods: Sixty-six immediate breast reconstructions were performed. Wide local excision (WLE), skin sparing mastectomy and subcutaneous mastectomy (SCM) were performed to 12, 20 and 34 patients, respectively. In all patients with WLE the reconstruction was performed with the latissimus dorsi (LD) miniflap. In other patients reconstructions were done with a free TRAM-flap (n=26) LD-flap (n=27) or with a prosthesis only (n=1)., Results: Major flap necrosis developed in four patients. Local recurrence rate was 8.3% in the group where nipple-areola-complex was removed and 7.1% in the group where nipple-areola-complex was saved. Metastases were found in 12.5 and 0%, respectively., Conclusion: SCM compared to skin sparing mastectomy may lead to an enhanced risk of immediate surgical complications, but does not threat the oncological safety. Saving the nipple-areola-complex in immediate breast reconstructions is possible in early breast cancer, if the tumour is not in the central part of the breast.

In human breast tissue, estrone (E(1)) and estradiol (E(2)) are mainly hydroxylated by cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) to 2-hydroxyestrogens (2-OHE(1/2)) and 4-hydroxyestrogens (4-OHE(1/2)), respectively. Several studies show that 4-OHE(1/2), but not 2-OHE(1/2), may act as a carcinogen and a high estrogen 4-/2-hydroxylation ratio appears to be a marker for the presence of neoplasms. In this study, we investigated the effects of several dioxin-like compounds on estrogen 2- and 4-hydroxylation in a malignant (MCF-7) and a nontumorigenic (MCF-10A) human mammary epithelial cell line. 2- and 4-methoxyestrogen (MeOE(1/2)) formations were used as measures of the 2- and 4-hydroxylation pathways, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 3,3'4,4',5,5'-hexachlorobiphenyl (PCB 169) concentration dependently induced 2-MeOE(1/2) formation and ethoxyresorufin-O-deethylation (EROD) activity through induced CYP1A1 expression in MCF-7 and MCF-10A cells. 2,3',4,4',5-pentachlorobiphenyl (PCB 118) had no such effect. Effects on CYP1B1 expression and 4-MeOE(1/2) formation were less pronounced; only TCDD caused an induction, whereas PCB 169 was a potent and selective inhibitor of 4-MeOE(1/2) formation (IC(50) 0.7 and 2.2 nM PCB 169 in MCF-7 and MCF-10A cells, respectively). MCF-10A cells were less responsive toward dioxin-like compounds and the apparent EC(50) values for CYP1A1 and CYP1B1 induction in this study were 10-100 fold higher than in MCF-7 cells. The constitutive 4-/2-MeOE(1/2) ratios were 2.99 +/- 0.78 and 0.93 +/- 0.40 in MCF-7 and MCF-10A, respectively. Incubation with dioxin-like compounds resulted in a concentration-dependent decrease in the 4-/2-MeOE(1/2) ratio, but an increase in potentially carcinogenic estrogen metabolites in both MCF-7 and MCF-10A cells. This indicates that even though the 4-/2-OHE(1/2) ratio may be used as indicator for the presence of neoplasms, it is readily lowered by dioxin-like compounds and its value as a prognostic parameter for cancer risk should be further examined.

Purpose: To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients., Patients and Methods: Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction., Results: No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV., Conclusion: Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.