Search

Supplementary Table 1 from The E2F-Regulated Gene Chk1 Is Highly Expressed in Triple-Negative Estrogen Receptor−/Progesterone Receptor−/HER-2− Breast Carcinomas

We previously showed that checkpoint kinase 1 (Chk1) and Claspin, two DNA-damage checkpoint proteins, were down-regulated by 1,25-dihydroxyvitamin D3, a known inhibitor of cell proliferation. In the present study, we aimed to investigate the transcriptional regulation of Chk1 and Claspin and to study their expression levels in human breast cancer tissue. Transient transfection experiments in MCF-7 breast cancer cells showed that promoter activities of Chk1 and Claspin were regulated by the E2F family of transcription factors. Subsequently, transcript levels of Chk1, Claspin, and E2F1 were determined by quantitative reverse transcriptase-PCR analysis in 103 primary invasive breast carcinomas and were compared with several clinicopathologic variables in breast cancer. A strong correlation was found between Chk1 and Claspin transcript levels. Transcript levels of Chk1, Claspin, and E2F1 were highest in histologic grade 3 tumors and in tumors in which the expression of estrogen receptor (ER) and progesterone receptor (PR) was lost. Moreover, Chk1 expression was significantly elevated in grade 3 breast carcinomas showing a triple-negative ER−/PR−/HER-2− phenotype compared with other grade 3 tumors. Further research is warranted to validate the use of Chk1 inhibitors in triple-negative breast carcinomas for which treatment strategies are limited at present. [Cancer Res 2007;67(14):6574–81]

PDF file - 272K

Purpose The aim of this study is (1) to investigate the prevalence rate of arm lymphedema, pain, impaired shoulder range of motion, strength and shoulder function one year after a sentinel lymph node biopsy (SLNB) for breast cancer and (2) to determine predictive factors for these complications. Methods A longitudinal study was performed. One hundred patients with a sentinel-lymph node negative breast cancer were included. All patients were measured before surgery and one year after. Arm lymphedema was measured with the perimeter, pain with the Visual Analogue Scale, shoulder range of motion with an inclinometer, strength with a handheld dynamometer and shoulder function with the Disability of Arm, Shoulder and Hand questionnaire. Patient-, breast cancer- and treatment-related variables were recorded. Results One year after surgery 8% of sentinel node-negative breast cancer patients had developed arm lymphedema. Fifty percent of patients had pain, 30% had an impaired shoulder range of motion, 8% had a decreased handgrip strength and 49% had an impaired shoulder function. Pain, shoulder range of motion, strength and shoulder dysfunctions changed significantly over one year (p < 0.001). Higher Body Mass Index is a predictive variable for shoulder dysfunctions one year post-SLNB. Conclusions Prevalence rate of lymphedema and other upper limb impairments may not be underestimated after SLNB. Pain, shoulder range of motion, handgrip strength and shoulder function change significantly up to one year compared to preoperative values in sentinel node-negative breast cancer patients.

Objective: To investigate the effect of myofascial therapy in addition to a standard physical therapy program for treatment of persistent arm pain after finishing breast cancer treatment. Design: Double-blinded (patient and assessor) randomized controlled trial. Setting: University Hospitals Leuven, Belgium. Patients: A total of 50 patients with persistent arm pain and myofascial dysfunctions after breast cancer treatment. Intervention: Over three months, all patients received a standard physical therapy program. The intervention group received in addition 12 sessions of myofascial therapy, and the control group received 12 sessions of placebo therapy. Main measurements: Main outcome parameters were pain intensity (primary outcome) (maximum visual analogue scale (VAS) (0-100)), prevalence rate of arm pain, pressure hypersensitivity (pressure pain thresholds (kg/cm(2)) and pain quality (McGill Pain Questionnaire). Measures were taken before and after the intervention and at long term (6 and 12months follow-up). Results: Patients in the intervention group had a significantly greater decrease in pain intensity compared to the control group (VAS -44/100 vs. -24/100, P=0.046) with a mean difference in change after three months between groups of 20/100 (95% confidence interval, 0.4 to 39.7). After the intervention, 44% versus 64% of patients still experienced pain in the intervention and control group, respectively (P=0.246). No significant differences were found for the other outcomes. Conclusion: Myofascial therapy is an effective physical therapy modality to decrease pain intensity at the arm in breast cancer survivors at three months, but no other benefits at that time were found. There were no long-term effects at 12months either.

Purpose To investigate the concurrent, face and content validity of an evaluation tool for Myofascial Adhesions in Patients after Breast Cancer (MAP-BC evaluation tool). Methods 1) Concurrent validity of the MAP-BC evaluation tool was investigated by exploring correlations (Spearman’s rank Correlation Coefficient) between the subjective scores (0 –no adhesions to 3 –very strong adhesions) of the skin level using the MAP-BC evaluation tool and objective elasticity parameters (maximal skin extension and gross elasticity) generated by the Cutometer Dual MPA 580. Nine different examination points on and around the mastectomy scar were evaluated. 2) Face and content validity were explored by questioning therapists experienced with myofascial therapy in breast cancer patients about the comprehensibility and comprehensiveness of the MAP-BC evaluation tool. Results 1) Only three meaningful correlations were found on the mastectomy scar. For the most lateral examination point on the mastectomy scar a moderate negative correlation (-0.44, p = 0.01) with the maximal skin extension and a moderate positive correlation with the resistance versus ability of returning or ‘gross elasticity’ (0.42, p = 0.02) were found. For the middle point on the mastectomy scar an almost moderate positive correlation with gross elasticity was found as well (0.38, p = 0.04) 2) Content and face validity have been found to be good. Eighty-nine percent of the respondent found the instructions understandable and 98% found the scoring system obvious. Thirty-seven percent of the therapists suggested to add the possibility to evaluate additional anatomical locations in case of reconstructive and/or bilateral surgery. Conclusions The MAP-BC evaluation tool for myofascial adhesions in breast cancer patients has good face and content validity. Evidence for good concurrent validity of the skin level was found only on the mastectomy scar itself.

Objective: To investigate the effects of myofascial techniques, in addition to a standard physical therapy programme for upper limb pain shortly after breast cancer surgery. Design: Double-blinded (patient and assessor) randomized controlled trial with two groups. Setting: University Hospitals Leuven, Belgium Patients: A total of 147 patients with unilateral axillary clearance for breast cancer. Intervention: All participants received a standard physical therapy programme starting immediately after surgery for four months. The intervention group received additionally eight sessions of myofascial therapy from two up to four months after surgery. The control group received eight sessions of a placebo intervention, including static hand placements at the upper body region. Main measurements: The primary outcome was prevalence rate of upper limb pain. Additionally, pain intensity (Visual Analogue Scale (VAS, 0-100)), pressure hypersensitivity (pressure pain thresholds (PPTs; kg/cm(2))) and pain quality (McGill Pain Questionnaire) were evaluated. All measurements were performed at 2 (=baseline), 4, 9 and 12months post-surgery. Results: At 4, 9 and 12months post-surgery, prevalence rates of pain, pain intensity and pain quality were comparable between the intervention and control group. PPT of the upper trapezius muscle was significantly higher in the intervention group at four months with a difference of -1.2 (-1.9 to -0.4) kg/cm(2), P=0.012). PPT of the supraspinatus muscle was significantly higher in the intervention group at four months (-0.7 (-1.4 to -0.1) kg/cm(2), P=0.021) and at nine months (-0.5 (-1.1 to 0.0), P=0.040). Conclusion: Myofascial therapy has no added beneficial effect as standard physical therapy modality in the postoperative stage.

Purpose To examine whether cognitive complaints after treatment for breast cancer are associated with detectable changes in brain activity during multitasking. Patients and Methods Eighteen patients who were scheduled to receive chemotherapy performed a functional magnetic resonance imaging multitasking task in the scanner before the start of treatment (t1) and 4 to 6 months after finishing treatment (t2). Sixteen patients who were not scheduled to receive chemotherapy and 17 matched healthy controls performed the same task at matched intervals. Task difficulty level was adjusted individually to match performance across participants. Statistical Parametric Mapping 8 (SPM8) software was used for within-group, between-group, and group-by-time interaction image analyses. Results Voxel-based paired t tests revealed significantly decreased activation (P < .05) from t1 to t2 at matched performance in the multitasking network of chemotherapy-treated patients, whereas no changes were noted in either of the control groups. At baseline, there were no differences between the groups. Furthermore, in contrast to controls, the chemotherapy-treated patients reported a significant increase in cognitive complaints (P < .05) at t2. Significant (P < .05) correlations were found between these increases and decreases in multitasking-related brain activation. Moreover, a significant group-by-time interaction (P < .05) was found whereby chemotherapy-treated patients showed decreased activation and healthy controls did not. Conclusion These results suggest that changes in brain activity may underlie chemotherapy-induced cognitive complaints. The observed changes might be related to chemotherapy-induced damage to the brain or reduced connectivity between brain regions rather than to changes in effort or changes in functional strategy. To the best of our knowledge, this is the first longitudinal study providing evidence for a relationship between longitudinal changes in cognitive complaints and changes in brain activation after chemotherapy.

Compared to volume/circumference measurements to diagnose lymphedema, thickening and disturbance of echogenicity of cutis and subcutis associated with the development of lymphedema is measured directly by ultrasonography. The aim of the present study was to investigate the evolution of thickness and echogenicity of cutis and subcutis of the lower and upper arm after axillary dissection for breast cancer and compare patients with and without arm lymphedema.Immediately after the surgery and at 6 and 12 months post-surgery, 42 patients received an ultrasonography of both arms, at the wrist, ventral and dorsal side of the lower arm, and biceps and triceps side of the upper arm. Thickness and echogenicity of cutis and subcutis were determined. Lymphedema was defined as 5.0% or more increase compare to the preoperative value. Eighteen patients had developed lymphedema of the lower arm, and 24 patients of the upper arm. Thickness of the cutis decreased significantly during the postoperative period on the healthy and affected side as well. The difference of cutis thickness between affected and healthy side increased postoperatively in patients with lymphedema and decreased in patients without lymphedema at the wrist and dorsal side of the lower arm. Patients with lymphedema had more frequent disturbance of echogenicity of the cutis at all measurement points. In exception of the triceps, thickness and echogenicity of the subcutis is less obvious disturbed. Sensitivity to detect arm lymphedema by ultrasonography was acceptable for increased subcutis thickness at the ventral lower arm and triceps and disturbed cutis echogenicity at the wrist (67%-100%). Sensitivity for the other measurements was bad. Specificity was for all measurements acceptable (59%-100%).Ultrasonography may be useful to diagnose lymphedema developing after axillary dissection for breast cancer. However, it cannot be used as a separate diagnostic test for lymphedema.

Purpose The aim of this study was to explore the treatment, patient, and impairment-related risk factors associated with upper limb dysfunctions in breast cancer survivors. Methods A cross-sectional study was performed in 274 women treated for breast cancer. The following risk factors were analysed by bivariable and multivariable analysis: 1) treatment-related variables (type of surgery, levels of lymph node dissected, radiotherapy, chemotherapy, hormone therapy and trastuzumab); 2) patient's related variables (age and Body Mass Index); 3) and finally impairment-related variables such as pain (intensity, quality and pressure hypersensitivity, signs of central sensitisation, the degree of pain catastrophizing and vigilance and awareness to pain), active ROM and upper limb strength were investigated. The dependent variable was upper limb function measured with the Disability of Arm, Shoulder and Hand (DASH) questionnaire. Additionally, a stepwise regression was performed. Results An impaired upper limb function was noted in 170 (62%) of patients. Mean time after surgery was 1.5 (1.6) years. From multivariable analysis, it appears that in particular certain pain characteristics such as pain intensity, pain quality, signs of central sensitisation and pain catastrophizing are contributing to upper limb dysfunctions after breast cancer treatment at long term. Additionally, higher age, shoulder ROM and handgrip strength are possible contributing factors. The stepwise regression analysis revealed that central sensitisation mechanisms alone can explain about 40% of the variance in upper limb function. Conclusions At long term, especially pain and central sensitisation mechanisms contribute to upper limb function in breast cancer survivors.

Question: What are the short-term and long-term preventive effects of manual lymph drainage (MLD), when used in addition to information and exercise therapy, on the development of lymphoedema after axillary dissection for breast cancer? Design: Randomised controlled trial with concealed allocation, blinded assessors and intention-to-treat analysis. Participants: Adults undergoing unilateral dissection for breast cancer were recruited, with 79 allocated to the experimental group and 81 to the control group. Intervention: The experimental group received guidelines about prevention of lymphoedema, exercise therapy and MLD. The control group received the same guidelines and exercise therapy, but no MLD. The interventions in both groups were delivered for 6 months. Outcome measures: The primary outcome was cumulative incidence of arm lymphoedema defined in four ways (≥ 200 ml, ≥ 2 cm, ≥ 5%, and ≥ 10% increase), which represent the difference in arm volume or circumference between the affected and healthy sides compared with the difference before surgery. Secondary outcomes included point prevalence of lymphoedema, change in arm volume difference, shoulder range of movement, quality of life and function. Results: Incidence rates were comparable between experimental and control groups at all follow-up measurements. Sixty months after surgery, the cumulative incidence rate for the ≥ 200 ml definition was 35% for the experimental group versus 29% for the control group (RR 0.89, 95% CI 0.51 to 1.54, p = 0.45); for the ≥ 2 cm definition 35% versus 38% (RR 0.93, 95% CI 0.59 to 1.45, p = 0.73); for the ≥ 5% definition 68% versus 53% (RR 1.28, 95% CI 0.97 to 1.69, p = 0.08) and for the ≥ 10% definition 28% versus 24% (RR 1.18, 95% CI 0.66 to 2.10, p = 0.57). The secondary outcomes were comparable between the groups at most assessment points. Conclusion: Manual lymph drainage may not have a preventive effect on the development of breast cancer-related lymphoedema in the short and long term. Trial registration: Netherlands Trial Register NTR 1055. [Devoogdt N, Geraerts I, Van Kampen M, De Vrieze T, Vos L, Neven P, Vergote I, Christiaens M-R, Thomis S, De Groef A (2018) Manual lymph drainage may not have a preventive effect on the development of breast cancer-related lymphoedema in the long term: a randomised trial. Journal of Physiotherapy 64: 245–254] Key words: Breast cancer, Prevention, Manual lymphatic drainage, Lymphoedema, Physical therapy

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. © 2013 The American Society of Human Genetics.

Purpose To investigate the clinical behavior of triple negative breast cancer (TNC), including age distribution, occurrence of LN (lymph node) invasion and prognosis in different histological subtypes. Methods For this cohort study we used data on 476 patients with newly diagnosed TNC at the University Hospitals Leuven (Belgium) between 1999 and 2009. Of these, 395 received upfront surgery, 68 neoadjuvant chemotherapy and 21 had metastases at diagnosis. Results Apocrine and invasive lobular TNC occur more often in older patients compared to IDC-NOS. Of the primarily operated patients with TNC, 35.1% has pathological LN involvement. There were no significant differences in nodal invasion between different histological subtypes, but most subtypes contained few patients. In contrast to previous reports, 6/14 of apocrine TNC had LN involvement. Disease free survival (DFS) was different in different histological subtypes, but group sizes were insufficient to be able to draw firm conclusions. Within the histologically ‘homogeneous’ IDC-NOS group with primary surgery and outcome data (n = 300), DFS with 3.5 year median follow-up decreased with increasing age, but chemotherapy and radiotherapy were much less frequently given with increasing age. In multivariable analysis, lower age, presence of LN involvement, lack of administration of chemotherapy and radiotherapy were significant predictors of relapse. Conclusion TNC is not a uniform disease. Different histological subtypes have different age distribution and behavior. The prognosis of the most common histological subgroup, IDC-NOS, is better in older patients, but this is counterbalanced by significantly decreased use of chemotherapy and radiotherapy.

Background Obesity (body mass index (BMI) >30) increases breast cancer (BC) risk and promotes BC metastases probably through high estrogen levels. A high BMI as a risk and prognostic factor is consistently reported in postmenopausal women. Obese women develop particularly hormone receptor positive, HER2 negative BC. In this study, we investigate the influence of BMI on the prognostic effect of the progesterone receptor (PR) in postmenopausal patients with estrogen receptor (ER) positive, HER2 negative BC. Patients and methods Women over 50 years of age diagnosed with primary operable BC between 2000 and 2012 at University Hospitals Leuven were retrieved from the database. Patients were subdivided into normal weight (25 and ≤30) and obese (>30). We investigated for each BMI category the distant metastasis free interval (DMFI) and BC specific survival (BCSS) by PR status. Apart from the total cohort, subgroup analysis was performed for luminal A (grade 1-2) and luminal B HER2 negative BC (grade 3). We used Fine and Gray’s competing risk regression for the analyses. Covariates were age at diagnosis, tumor size, lymph node status, and therapy. Results In total, 3227 patients were analyzed for DMFI. For BCSS, 3192 patients were analyzed as patients with unknown cause of death were excluded from the analysis. 2395 of all patients had luminal A and 832 had luminal B HER2 negative BC (Table 1). Median time of follow-up was 6.5 years. Table 1: Percentage of luminal A and luminal B patients per BMI category BMI25 and ≤30BMI >30Luminal A1105 (76%)820 (75%)470 (70%)Luminal B355 (24%)278 (25%)199 (30%)BMI: body mass index BMI interacts with the prognostic effect of PR for DMFI and BCSS in luminal HER2 negative BCs. Only patients with BMI Table 2: Multivariate analysis for DMFI and BCSS for PR positive versus PR negative in the 3 BMI categories in the total and the luminal B cohort. DMFI (HR, 95% CI)BCSS (HR, 95% CI)Total cohort BMI 25 and ≤301.24, 0.59 to 2.600.95, 0.40 to 2.25BMI >300.70, 0.33 to 1.490.53, 0.21 to 1.33luminal B BMI 25 and ≤301.23, 0.44 to 3.481.02, 0.36 to 2.85BMI >300.82, 0.31 to 2.200.61, 0.18 to 2.00BCSS: breast cancer specific survival, BMI: body mass index, CI: confidence interval, DMFI: distant metastasis free interval, HR: hazard ratio Conclusion Normal weight patients have a reduced risk of developing distant metastases and of BC-related death if the tumor is PR positive compared to PR negative BC. No difference between PR positive and PR negative cases was observed in overweight BC patients. This BMI-dependent prognostic effect of PR was limited to luminal B BC patients. Citation Format: Kathleen Van Asten, Anneleen Lintermans, Annouschka Laenen, Chantal Remmerie, An Poppe, Giuseppe Floris, Hans Wildiers, Marie-Rose Christiaens, Patrick Neven. The body mass index interacts with the prognostic effect of the progesterone receptor in patients with a luminal HER2 negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-02.

Lymph node involvement is the most important prognostic factor in breast cancer. It is a multifactorial event determined by patient and tumour characteristics. The purpose of this study was to determine clinical and pathological factors predictive for axillary lymph node metastasis (ALNM) in patients with early breast cancer and to build a model to portend lymph node involvement.We evaluated 1300 consecutive patients surgically treated in our institution (2007-2009) for cT1-T2 invasive breast cancer. The patient and tumour characteristics evaluated included: age at diagnosis, number of foci, histologic grade, location, tumour size, histologic subtype, lymphovascular invasion (LVI), estrogen-receptor (ER), progesterone-receptor (PR) and Her-2 status. Univariate and multivariate analyses were performed. Factors significantly associated with ALNM by univariate analysis plus histologic subtype were included in the multivariate analysis.By univariate analysis, the incidence of ALNM was significantly associated with the presence of LVI (P 0.0001), larger tumour size (P 0.0001), higher histologic grade (P 0.0001), retroareolar or lateral location in the breast (P 0.0001), multiple foci (P = 0.0002) and in patients who underwent an axillary lymph node dissection. We found no effect of age, ER⁄PR nor HER-2 status. By multivariate analysis, ALNM was significantly associated with the presence of LVI (P 0.0001), larger tumour size (P 0.0001), axillary lymph node dissection (P = 0.0003), retroareolar and lateral tumour location in the breast (P = 0.0019) and the presence of multiple foci (P = 0.0155).LVI and tumour size emerged as the most powerful independent predictors of ALNM, followed by the location of the tumour in the breast and the presence of multiple foci.

Introduction Worldwide, breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death, accounting for 23% of total cancer cases and 14% of cancer deaths. Lymph node involvement is the most important prognostic factor and varies with several tumor and patient characteristics (ie, age at diagnosis, tumor size, tumor type, tumor grade, lymphovascular invasion, multifocality, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 [HER-2] status). Factors o be considered in clinical decision making include not only

PURPOSE: Besides pain, myofascial dysfunctions may contribute to the presence of upper limb impairments such as impaired range of motion, decreased strength, lymphedema, and altered postures and kinematics. Therefore, the aim of this study was to investigate the effect of myofascial therapy in addition to a standard physical therapy program for treatment of upper limb dysfunctions in breast cancer survivors. METHODS: Fifty women treated for a unilateral breast cancer with pain and myofascial dysfunctions at the upper limb region. The intervention group received 12 sessions of myofascial therapy consisting of release techniques on myofascial trigger points and adhesions in addition to a standard physical therapy program for 3 months. The control group received 12 sessions of a placebo intervention in addition to the same standard physical therapy program during the 3 months. Outcome parameters are active shoulder range of motion (inclinometer); arm lymphedema (perimeter); upper limb strength (handheld dynamometer); scapular statics and dynamics (acromion-table and pectoralis minor index, inclinometer); shoulder function (Disability of Shoulder, Arm and Hand questionnaire); and quality of life (Short Form 36). Measures were taken before and after the intervention at 6 and 12 months follow-up. RESULTS: No differences between groups were found for all outcome parameters over the course of 1 year. However, overall beneficial effects of the standard physical therapy program for active shoulder range of motion and shoulder function were found in both groups up to 1 year follow-up. CONCLUSION: Myofascial therapy has no additional beneficial effect for improvement of upper limb function in breast cancer survivors. ispartof: Supportive Care In Cancer vol:25 issue:7 pages:2119-2127 ispartof: location:Yokohama (Japan) status: published

We correlated serum 25-hydroxyvitamin D3 (25OHD) levels with tumor characteristics and clinical disease outcome in breast cancer patients and assessed the impact of genetic determinants of vitamin D insufficiency. We collected serum from 1800 early breast cancer patients at diagnosis, measured 25OHD by radioimmunoassay (RIA), and determined genetic variants in vitamin D-related genes by Sequenom. Multivariable regression models were used to correlate 25OHD levels with tumor characteristics. Cox proportional hazard models were used to assess overall survival (OS), disease-specific survival (DSS), and disease-free interval (DFI). Lower 25OHD serum levels significantly correlated with larger tumor size at diagnosis (P = 0.0063) but not with lymph node invasion, receptor status, or tumor grade. Genetic variants in 25-hydroxylase (CYP2R1) and vitamin D-binding (DBP) protein significantly determined serum 25OHD levels but did not affect the observed association between serum 25OHD and tumor size. High serum 25OHD (>30 ng/mL) at diagnosis significantly correlated with improved OS (P = 0.0101) and DSS (P = 0.0192) and additionally had a modest effect on DFI, which only became apparent after at least 3 years of follow-up. When considering menopausal status, serum 25OHD had a strong impact on breast cancer-specific outcome in postmenopausal patients [hazards ratios for 25OHD >30 ng/mL versus ≤30 ng/mL were 0.15 (P = 0.0097) and 0.43 (P = 0.0172) for DSS and DFI, respectively], whereas no association could be demonstrated in premenopausal patients. In conclusion, high vitamin D levels at early breast cancer diagnosis correlate with lower tumor size and better OS, and improve breast cancer-specific outcome, especially in postmenopausal patients.

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Summary Background The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. Methods The EORTC 10801 trial was open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. Findings After a median follow-up of 22·1 years (IQR 18·5–23·8), 175 patients (42%) had distant metastases in the MRM group versus 207 (46%) in the BCT group. Furthermore, 506 patients (58%) died (232 [55%] in the MRM group and 274 [61%] in the BCT group). No significant difference was observed between BCT and MRM for time to distant metastases (hazard ratio 1·13, 95% CI 0·92–1·38; p=0·23) or for time to death (1·11, 0·94–1·33; 0·23). Cumulative incidence of distant metastases at 20 years was 42·6% (95% CI 37·8–47·5) in the MRM group and 46·9% (42·2–51·6) in the BCT group. 20-year overall survival was estimated to be 44·5% (95% CI 39·3–49·5) in the MRM group and 39·1% (34·4–43·9) in the BCT group. There was no difference between the groups in time to distant metastases or overall survival by age (time to distant metastases: vs ≥50 years 1·16 [0·90–1·50]; overall survival vs ≥50 years 1·10 [0·89–1·37]). Interpretation BCT, including radiotherapy, offered as standard care to patients with early breast cancer seems to be justified, since long-term follow-up in this trial showed similar survival to that after mastectomy. Funding European Organisation for Research and Treatment of Cancer (EORTC).

Background. Lymphedema occurs frequently after axillary dissection for breast cancer and causes significant physical and psychosocial problems. To plan the treatment for lymphedema and monitor the patient's progress, arm swelling and arm function need to be assessed. Objective. The purpose of this study was to investigate the reliability (test-retest, internal consistency, measurement variability) and validity (content and construct) of data obtained with the Lymphoedema Functioning, Disability and Health questionnaire (Lymph-ICF). Methods. The Lymph-ICF is a descriptive and evaluative tool and consists of 29 questions about impairments in function, activity limitations, and participation restrictions of patients with breast cancer and arm lymphedema. The questionnaire is divided into 5 domains: physical function, mental function, household activities, mobility activities, and life and social activities. Reliability and validity were examined on 60 patients with lymphedema and 30 patients without lymphedema. Results. Intraclass correlation coefficients for test-retest reliability ranged from .65 to .93. Cronbach alpha coefficients for internal consistency were higher than .70. There were no systematic changes from the first test to the second test, and measurement variability was acceptable (standard errors of measurement = 4.8-12.5). Content validity was good because all questions were understandable for all participants, the scoring system (visual analog scale) was clear for 88% of the participants, and all complaints due to arm lymphedema were mentioned by 85% of the participants. Construct validity was good. There was good convergent validity because 5 expected domains of the Lymph-ICF had the strongest correlation with 5 expected domains of the 36-Item Short-Form Health Survey questionnaire (SF-36). Thus, the 5 hypotheses assessing convergent validity were accepted. There was acceptable divergent validity because 3 of 5 hypotheses assessing divergent validity were accepted. There was good known-groups validity because patients with lymphedema had a higher total score on the Lymph-ICF and had a higher score on each domain and on each question (except one) compared with patients without lymphedema. Conclusion. The Lymph-ICF is a reliable and valid questionnaire to assess impairments in function, activity limitations, and participation restrictions of patients with arm lymphedema after axillary dissection for breast cancer.

To evaluate retrospectively the accuracy of integrated PET/CT, against PET, CT, or conventional staging in breast cancer. Seventy consecutive biopsy proven clinical stage IIB and III breast cancer patients were included. Descriptive statistics of integrated PET/CT for the primary tumor, nodal status and metastasis detection were compared to PET, CT with contrast, and conventional staging (biochemistry, chest X-ray, liver ultrasound, and bone scintigraphy). Sensitivity of PET/CT for primary tumor and nodal status was 97.1% and 62.5%, respectively. Specificity and negative predictive value for nodal status were 100% and 66.6%, respectively. The values for conventional staging for nodal involvement were 100% and 85.7% with a sensitivity of 87.5%. PET/CT showed metastatic disease in seven women despite normal conventional staging. PET/CT is able to visualize most clinical stage IIB and III primary breast cancers. PET/CT is superior to conventional staging for detecting internal mammary chain nodes and metastatic disease, but not for axillary staging. Future studies will have to test whether therapy adjustment based on PET/CT has the potential to improve survival.

Purpose To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS). Patients and Methods The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively. Results In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer–related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI − PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group. Conclusion The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care.

This retrospective incidence-based cost-of-illness analysis aims to quantify the costs associated with female breast cancer in Flanders for the year prior to diagnosis and for each of the 5 years following diagnosis. A bottom-up analysis from the societal perspective included direct health care costs and indirect costs of productivity loss due to morbidity and premature mortality. A case-control study design compared total costs of breast cancer patients with costs of an equivalent standardised population with a view to calculating the additional costs that can be attributed to breast cancer. Total average costs of breast cancer amounted to 107,456europer patient over 6 years. Total costs consisted of productivity loss costs (89% of costs) and health care costs (11% of costs). Health care costs did not vary with age at diagnosis. Health care costs of breast cancer patients converged with those of the general population at 5 years following diagnosis. Patients with advanced breast cancer stadia had higher health care costs. Cost estimates provided by this analysis can be used to determine priorities for, and inform, future research on breast cancer. In particular, attention needs to be focussed on decreasing productivity loss from breast cancer.

The purpose of this article is to provide a systematic review of Combined Physical Therapy, Intermittent Pneumatic Compression and arm elevation for the treatment of lymphoedema secondary to an axillary dissection for breast cancer. Combined Physical Therapy starts with an intensive phase consisting of skin care, Manual Lymphatic Drainage, exercises and bandaging and continues with a maintenance phase consisting of skin care, exercises, wearing a compression sleeve and Manual Lymphatic Drainage if needed. We have searched the following databases: PubMed/MEDLINE, CINAHL, EMBASE, PEDro and Cochrane. Only (pseudo-) randomised controlled trials and non-randomised experimental trials investigating the effectiveness of Combined Physical Therapy and its different parts, of Intermittent Pneumatic Compression and of arm elevation were included. These physical treatments had to be applied to patients with arm lymphoedema which developed after axillary dissection for breast cancer. Ten randomised controlled trials, one pseudo-randomised controlled trial and four non-randomised experimental trials were found and analysed. Combined Physical Therapy can be considered as an effective treatment modality for lymphoedema. Bandaging the arm is effective, whether its effectiveness is investigated on a heterogeneous group consisting of patients with upper and lower limb lymphoedema from different causes. There is no consensus on the effectiveness of Manual Lymphatic Drainage. The effectiveness of skin care, exercises, wearing a compression sleeve and arm elevation is not investigated by a controlled trial. Intermittent Pneumatic Compression is effective, but once the treatment is interrupted, the lymphoedema volume increases. In conclusion, Combined Physical Therapy is an effective therapy for lymphoedema. However, the effectiveness of its different components remains uncertain. Furthermore, high-quality studies are warranted. The long-term effect of Intermittent Pneumatic Compression and the effect of elevation on lymphoedema are not yet proven.

Objective: To explore how female breast cancer patients experience work incapacity during the treatment and return-to-work phases and how interactions between patients and stakeholders affect this experience. Method: Database search for full text articles published between January 1995 and January 2008 that focused on employed female breast cancer patients, factors related to work incapacity, and returning to work. Only results based on self-report data were included. Studies focusing on treatment, financial factors, rate of return, or absence were excluded. Results: Six articles met the inclusion criteria. Women with breast cancer receive varied reactions but little advice about returning to work. Women were primarily concerned with disclosing the diagnosis to their employer and to relatives. Uncertainties about physical appearance, ability to work, and possible job loss affected the women's decisions about working during the treatment phase. After treatment, most women wanted to regain their ‘normal life’, but concentration and arm or fatigue problems potentially interfered. Although supportive work environments were helpful, the individual needs of women differed. Employers and employees need to find a balance in defining accommodating work. Many women received favourable support, but some reported feeling discriminated against. Many women re-evaluated the role of work in their lives after being confronted with breast cancer. Conclusion: Work adjustments could help women to keep their jobs during illness and recovery. To resolve women's concerns about returning to work, employers, physicians, and insurance institutions should consider increasing and improving communication with breast cancer patients and playing a more active and supportive role. Copyright © 2009 John Wiley & Sons, Ltd.

Aim: Basal-like breast tumours, as defined by microarrays, carry a poor prognosis and therapeutic options are limited to date. Often, these tumours are defined as oestrogen receptor (ER) negative/progesterone receptor (PR) negative/human epidermal growth factor receptor 2 (HER-2) negative (triple negative) by immunohistochemistry (IHC), but a more complete definition should include expression of basal cytokeratins (CK5/6, CK14 or CK17) and/or human epidermal growth factor receptor 1 (HER-1). The aim of this study was to investigate to what extent CK5/6 and HER-1 characterise the group of triple negative breast cancers. Methods: Expression of CK5/6 and HER-1 was studied by IHC in 25 triple negative breast carcinomas and 32 grade-matched, non-triple-negative controls. All 57 cases were further subjected to fluorescence in situ hybridisation to investigate HER-1 gene copy number. Results: CK5/6 and HER-1 expression was most frequent in triple negative tumours: 22 out of 25 cases (88.0%) expressed at least one of these markers (60.0% CK5/6 positive and 52.0% HER-1 positive). In the control group, CK5/6 and HER-1 expression was found in ER-negative but not in ER-positive tumours (ER negative/PR negative/HER-2 positive tumours: 20.0% CK5/6 positive and 46.7% HER-1 positive). HER-1 gene amplification was found in five cases only: four triple negative (16.0%) and one ER-negative control (ER negative/PR negative/HER-2 positive, 6.7%). Of interest, all five HER-1 amplified cases showed a remarkably homogeneous HER-1 expression pattern. Conclusion: Expression of CK5/6 and HER-1 is frequent in ER-negative breast cancers, in triple negative and in non-triple negative tumours. In a minority of cases, HER-1 overexpression may be caused by HER-1 gene amplification. Further studies are needed to investigate whether such cases might benefit from anti-HER-1 therapy

This prospective study assessed the endometrial effects of fulvestrant, a pure estrogen-receptor antagonist, in postmenopausal women with breast cancer. This single-center study enrolled postmenopausal patients who had an intact uterus at baseline with progressive metastatic breast cancer on tamoxifen followed by an oral aromatase inhibitor (AI). Fulvestrant (250 mg) was administered every 28 +/- 3 days via IM injection. Transvaginal ultrasonography (TVUS) was performed at baseline and after 3 months of therapy. Primary and secondary endpoints were changes from baseline in double endometrial thickness (DET) and uterine volume (UV), respectively. No interventions were performed on any asymptomatic uterine abnormalities that were detected at baseline. In total, 32 women were enrolled. Five patients had no repeat TVUS because of early progression before 3 months, leaving 27 evaluable patients for final analysis. After 3 months therapy, mean DET had significantly decreased by 23.08% (P = 0.010). Mean UV also decreased by 10.88%, although this change was not significant (P = 0.119). After 3 months of therapy, none reported vaginal bleeding, there were no changes noted in most of the uterine pathologies present at baseline and no new uterine abnormalities were detected. We observed that 3 months of fulvestrant treatment resulted in a significant decrease in endometrial growth and a non-significant decrease in UV in postmenopausal women with metastatic breast cancer previously exposed to tamoxifen and AIs. Furthermore, no new uterine pathologies were detected, indicating that fulvestrant behaves as a pure antiestrogen at the uterine level.

Patients and methods All patients with non-metastatic operable breast cancer from UZ Leuven diagnosed between January 1, 2000 and December 31, 2013 were included (n=7020). For statistical analysis, linear models and logistic regression were used to study respectively the association between BMI and age at diagnosis and BMI and breast cancer phenotype by menopausal status. Where necessary, a correction for the relation between BMI and age will be applied, based on publicly available data from the Belgian Health Interview Surveys.

Matrix metalloproteinases (MMPs), in particular the gelatinases MMP2 and MMP9, are important mediators of tumour invasion and metastasis. We examined whether plasma gelatinase levels could predict lymph node metastasis in breast cancer patients. Further, we investigated the relationship of plasma gelatinase levels with Her2/neu expression, recently acknowledged as an important prognostic factor for recurrence, and with various clinicopathological factors. Preoperative plasma samples from 81 breast cancer patients were collected. Total and active gelatinase levels were measured by enzyme immunoassays and activity assays, respectively. Neither total nor active plasma MMP2 levels correlated with nodal status or with any of the classical clinicopathological factors including histological tumour type, tumour size and grade and hormone receptor status. Patients with Her2/neu overexpressing tumours showed an increase of 27% (P=0.007) in plasma MMP2 activity, but not in total MMP2, compared with patients without overexpression. MMP9 levels, total and active, did not correlate with any of the investigated variables. In contrast to MMP9, total MMP2 levels correlated significantly with active MMP2 levels. In summary, total and active plasma gelatinase levels failed to identify high risk for axillary lymph node metastasis. Active plasma MMP2 was significantly increased in patients with Her2/neu overexpressing tumours, suggesting a role for Her2/neu in the signalling pathways of MMP2 activation in carcinogenesis. However, this increase was too small to be of clinical use. Furthermore, no relationship was found between plasma gelatinase levels, total or active, and any of the clinicopathological prognostic factors.

The objective of the sentinel lymph node procedure in breast cancer is to perform an accurate axillary staging and provide good local control, while sparing the patients the morbidity of an axillary lymph node dissection. Since its routine clinical use, questions were raised concerning the implications for local and systemic adjuvant treatment. This review provides an update of the recent literature.As a result of a more detailed histopathologic work-up of the sentinel lymph node, higher rates of lymph node metastases are detected. This leads to an upstaging of a subset of node-negative patients and an increase in the overall percentage of node-positive patients. However, the clinical implications of micrometastases and isolated tumor cells remain unclear. Furthermore, sentinel lymph nodes may be found in the internal mammary lymph node chain but the treatment of these nodes is subject of debate.Current guidelines recommend axillary lymph node dissection in patients with a positive sentinel node. The surgical removal of the internal mammary lymph node is only indicated in the context of a clinical trial. Radiation therapy of the axilla is an acceptable alternative for patients who refuse an axillary lymph node dissection (clinical trial). The value of radiotherapy to the internal mammary lymph node has never been established. Systemic treatment decisions in patients with a macrometastasis or micrometastasis in the sentinel lymph node follow the guidelines of node-positive patients, whereas in patients with isolated tumor cells only, guidelines for node-negative patients are followed. The results of ongoing clinical trials will be important for the development of further guidelines.

In oestrogen receptor-positive (ER+) breast cancer, HER-2/neu and the progesterone receptor (PR) are inversely associated. This explains a lower response to anti-oestrogens if ER+ breast cancers are HER-2/neu positive. One randomized study however, showed that premenopausal women with an ER+ breast cancer respond to anti-oestrogens independent of HER-2/neu. We therefore hypothesized an age-related association between HER-2/neu and PR in ER+ breast cancers. Receptors for ER, PR and HER-2/neu were analysed by immunohistochemistry (IHC). A uni- and multivariate analyses was carried out to assess this relationship in 1104 women with an ER+ breast cancer. We observed an inverse association between HER-2/neu and PR only after age 45. There were 173 women of age 45 years. In multivariate analysis, only tumour grade (p=0.005) but not PR status was associated with HER-2/neu in women age 45 years group, both PR status (p=0.001) and tumour grade (p=0.001) were independently associated with HER-2/neu. In ER+ breast cancers from women age>45, PR was positive in 76.9% if HER-2/neu negative but in 53.4% if HER-2/neu positive (p 45 years but not in women age

Endocrine treatments of breast cancer patients antagonize estrogen and may lead to consequences of estrogen deprivation including menopausal symptoms. We analyzed the changes in frequency and severity of menopausal symptoms in patients receiving tamoxifen or aromatase inhibitors and identified factors influencing these symptoms. One hundred and eighty-one consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. A menopause symptom questionnaire covering vasomotor, atrophic, psychological, cognitive and somatic symptoms was filled in at baseline, and after 1 and 3 months of therapy. Both first-line tamoxifen and aromatase inhibitors induced an increase in the occurrence and severity of hot flashes (p

For treatment of early breast cancer in older women, little evidence is available from randomised trials. We conducted a randomised trial comparing modified radical mastectomy (MRM) with tamoxifen (TAM) as the sole initial therapy in 164 patients aged greater than or equal to70 years with operable breast cancer. 82 were treated by MRM and 82 with TAM. Survival curves were estimated using the Kaplan-Meier method: multivariate analyses were performed using the Cox's proportional hazards model. Endpoints included survival, time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. After a median follow-up of approximately 10 years, there was a significantly decreased time to progression in the TAM only group (logrank P < 0.0001) and significantly shorter time to local progression within the TAM group (logrank P < 0.0001). Overall survival of the two groups was similar. The results indicate that tamoxifen alone leads to an unacceptably high rate of local progression or relapse. (C) 2003 Elsevier Science Ltd. All rights reserved.

Compared to European women, breast cancers in African women present at a younger age, with a higher tumor grade and are more often estrogen receptor (ER)/progesterone receptor (PR) negative. We here investigate the histopathological and immunohistochemical characteristics (ER, PR and human epidermal growth receptor 2 (HER2)) and the proportion of triple negative (Tneg) invasive breast cancers from an unselected series of patients diagnosed in Kinshasa, and compare them to a population of Caucasian women with a palpable breast cancer.From 2010 till 2013, during the first breast cancer awareness campaign, organized in Kinshasa, 87 patients were diagnosed with invasive breast cancer. Diagnose was based on core biopsy. The control group consisted of Caucasian women (University Hospitals of Leuven, Belgium) with a palpable mass, diagnosed between 2000 till 2009, treated with surgery of which the histopathological and immunohistochemical characteristics were collected on excision specimens. Each patient in the Kinshasa group was matched based on age and tumor size to one or more patients of the Leuven database. Differences between both groups with respect to hormone receptors (ER, PR, HER2, Tneg) or grade are presented as relative risks (RR). The analysis is based on a log-binomial model accounting for clustering through matching by a random intercept for cluster. Differences between both groups with respect to hormone receptors correcting for grade is performed by the inclusion of grade as a covariate in the model.After adjusting for age, tumor volume and tumor grade, ER was more frequently negative (RR = 0.71, p0.001), with a trend in the same direction for PR (RR = 0.87, p = 0.057), and HER2 more often positive (RR = 1.60, p = 0.015) compared to the group from the University Hospitals of Leuven. There was no difference in the proportion of breast cancers being triple negative. Sub-analysis showed that the higher HER2 positive rate was only observed in older patients (≥50y: RR = 2.07, p = 0.007) whereas no difference in HER2 positive rate was found in younger patients (50y: RR = 1.30, p = 0.358). A higher ER negative rate was observed in both age groups, however more pronounced in older patients (≥50y: RR = 0.64, p = 0.001;50y: RR = 0.79, p = 0.018).Breast cancer in women of Kinshasa presents at younger age and is more aggressive (more frequently ER negative and HER2 positive) compared to Caucasian women and this is more pronounced in older women (50y). Only the ER results were concordant with the results of two similar studies (comparing an African with a European group), but were different when compared to studies on African-American women with breast cancer. This information is very important considering the treatment option: as more tumors are ER negative, endocrine therapy cannot be given while chemotherapy is often too expensive.

Aromatase inhibitors (AIs) frequently induce or enhance musculoskeletal problems (AI-induced musculoskeletal syndrome (AIMSS)) which sometimes are debilitating. Apart from low oestrogen levels, underlying mechanisms are unknown and likely multiple. We previously hypothesised a role for the growth hormone/insulin like growth factor-I (IGF-I) axis. Here, we report the effect of tamoxifen and AI on IGF-I, IGF binding protein-3 (IGFBP-3) and oestrogen levels from a prospective study.Postmenopausal women with an early breast cancer scheduled to start adjuvant endocrine therapy with an AI or tamoxifen were recruited. A rheumatologic questionnaire was completed and serum was collected for assessment of IGF-I, IGFBP-3 and oestrogen levels. Re-evaluation was done after 3, 6 and 1 2months of therapy.84 patients started on tamoxifen (n=42) or an AI (n=42). 66% of the latter group experienced worsening of pre-existing or de novo complaints in joint and/or muscle, compared to 29% of tamoxifen-treated patients. AI therapy resulted in elevated IGF-I levels with a statistically significant increase at 6months (p=0.0088), whereas tamoxifen users were characterised by a decrease in IGF-I levels at all follow-up times (p0.0004). No effect on IGFBP-3 was seen in the latter group. AI-users, however, showed decreased IGFBP-3 levels at 12 months (p=0.0467). AIMSS was characterised by a decrease in IGFBP-3 levels (p=0.0007) and a trend towards increased IGF-I/IGFBP-3 ratio (p=0.0710).These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the growth hormone (GH)/IGF-I axis.

Background : In recent years T pot (potential doubling time) has been measured before treatment in human tumors in an attempt to estimate the proliferation taking place during a course of irradiation. T pot is defined as T s / LI , where T s is the duration of DNA synthesis and LI is the labeling index (proportion of cells synthesizing DNA). T s is more difficult to measure than LI , so the question arises whether variation introduced during the determination of T s is compensated by the theoretically better relevance of the quotient T pot than of LI alone. It is not clear from comparisons with clinical outcome whether T pot is a useful indicator of proliferation or whether LI is more prognostic, as suggested by a currently ongoing multicenter analysis elsewhere. Therefore, we investigated intercomparisons between T pot and its components LI and T s in two in their proliferation rates contrasting types of tumor where multiple biopsies were taken from each tumor. Materials and methods : Sixty patients with esophageal carcinoma and 57 patients with breast cancer were included in this study. All patients were injected with IUdR 6–8 h before surgery. From each tumor three to five biopsies were taken at surgery. Using flow cytometry, LI and T s were measured on all biopsies in order to calculate T pot . Logarithmic transformations of the distributions were used to examine correlations. Kappa-tests were used to assess how reliable an LI value could be in predicting the corresponding T pot . Results : T s and LI were not completely independent, based on the within-tumor coefficients of variation ( CV w ). The ratio of between-tumor coefficient of variation ( CV b ) to the CV w suggested that the discriminative power of T pot was higher than LI for esophagus, but the reverse in breast tumors, which had a larger range. Pearson correlation coefficients were high for log T pot versus log LI in both types of tumor, but the predictive power was low, as shown by κ -values of only 0.3–0.41 starting with LI and trying to predict the corresponding value of T pot . Increasing widths of a central `gray zone' were investigated for improved discrimination between fast and slow proliferation. Multiples of the within-tumor standard deviation, equally on each side of the median, were used to vary the width of the gray zone. Without a gray zone no more than 70% successful matching was obtained in esophagus tumors, compared with 80% in breast tumors. However, by excluding about half of the esophageal tumors an 80% success rate was achieved. In breast tumors over 90% matching was obtained more easily, keeping 80% of the tumors classifiable. For both tumor types correlations between T s and T pot were weak, with a trend towards short T s associated with short T pot and also with low LI . The latter correlation was significant for esophageal tumors and resulted in T pot values having a smaller range than the LI s. Conclusion : Although there were good correlation coefficients between T pot and LI , the predictive power of either from the other was not reliable, except by excluding a significant number of tumors close to the medians. The predictive value of LI for T pot was higher for breast tumors because the spread in cell kinetic measurements was wide. Until more clinical data become available on outcome in comparison with LI or T pot , it is still worthwhile to measure T pot and to assess the prognostic value of both LI and T pot in relation to outcome.

Completion axillary lymph node dissection (cALND) is the golden standard if breast cancer involves the sentinel lymph node (SLN). However, most non-sentinel lymph nodes (NSLN) are not involved, cALND has a considerable complication rate and does not improve outcome. We here present and validate our predictive model for positive NSLNs in the cALND if the SLN is positive. Consecutive early breast cancer patients from one center undergoing cALND for a positive SLN were included. We assessed demographic and clinicopathological variables for NSLN involvement. Uni- and multivariate analysis was performed. A predictive model was built and validated in two external centers. 21.9% of 470 patients had at least one involved NSLN. In univariate analysis, seven variables were significantly correlated with NSLN involvement: tumor size, grade, lymphovascular invasion (LVI), number of positive and negative SLNs, size of SLN metastasis and intraoperative positive SLN. In multivariate analysis, LVI, number of negative SLNs, size of SLN metastasis and intraoperative positive pathological evaluation were independent predictors for NSLN involvement. The calculated risk resulted in an AUC of 0.76. Applied to the external data, the model was accurate and discriminating for one (AUC = 0.75) and less for the other center (AUC = 0.58). A discriminative predictive model was constructed to calculate the risk of NSLN involvement in case of a positive SLN. External validation of our model reveals differences in performance when applied to data from other institutions concluding that such a predictive model requires validation prior to use. (C) 2014 Elsevier Ltd. All rights reserved

Since the routine clinical use of the sentinel lymph node (SLN) procedure, questions have been raised concerning an increase in the overall percentage of node-positive patients. The goal of our study was to compare the sensitivity of the SLN procedure and the axillary lymph node dissection (ALND) for the identification of positive lymph nodes in breast cancer. The incidence of axillary node metastasis in SLNB and ALND specimens from patients undergoing operative treatment of a primary breast carcinoma was compared retrospectively. Logistic regression models were used to analyze the effect of various predictors on the presence of positive lymph nodes. We constructed a multivariate model including the procedure and these predictors that have shown to be related to lymph node involvement in univariate analysis. The probability of finding positive lymph nodes was thus calculated in both groups correcting for relevant predictors of lymph node involvement. The SLNB group included 830 patients, the ALND group 320. In a multivariate analysis, adjusting for the number of foci, tumor location in the breast, tumor size, LVI, ER, PR, tumor grade and histological subtype, the probability of finding positive lymph nodes was higher with SLNB procedure than with an ALND. However, this difference was not statistically significant (OR 0.7635; CI 0.5334-1.0930, p 0.1404). For comparable tumors, SLNB procedure is at least as sensitive as ALND for detecting positive lymph nodes.

CC-chemokine ligand 5 (CCL5) was measured in plasma of 238 patients with breast cancer and in serum of 149 of these patients. Mean circulating CCL5 levels tended to be higher in patients with lymph-node-positive breast cancer, larger tumour sizes, the presence of lymphovascular invasion, and multifocal tumours. Additionally, circulating CCL5 levels were higher in the order of stages III, II, and I.The addition of circulatingCCL5 concentration to known clinicopathological predictors for lymph node involvement did not allow more precise prediction of the lymph node status.These results suggest that CCL5 is a biomarker for tumour load rather than for lymph node involvement.As such, it might be helpful to identify patientswith escape fromimmunosurveillance who will benefit from therapies to restore immune function. ispartof: ISRN Immunology vol:2013 status: published

When researching the literature, many differences within surgical techniques for breast conservation, tumour excision and axillary dissection are described in the smallest detail. Most authors have their own preferences but little clinical research has been done to evaluate the impact of those differences on outcome: local control, cosmesis, complications or costs. Even when prospective, randomized clinical trial protocols provide many instructions to perform the surgery, the case report forms almost never document the surgery actually performed. This is in contrast to radiotherapy and chemotherapy regimens, which have had higher standards of quality of care implemented. The development of more detailed and standardized procedural information should lead to more accurate and specific information, which can be easily transferred in a learning process, and enable more reliable clinical research. Documentation and guidelines for surgery are essential tools in implementing a process of quality audit for a type of surgery where accuracy is essential.

Purpose We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer–specific death, and risk of a second breast cancer in women with a first breast cancer. Patients and Methods From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer–specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. Results CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor–positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer–specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor–positive first breast cancer only. Conclusion Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer–specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

BACKGROUND: Improvements in treatment have resulted in an increasing number of cancer survivors potentially being able to return to work after medical treatment. In this paper we focus on the considerations regarding return to work (RTW) of breast cancer absentees in the Belgian context and how these considerations are related to reactions from their social environment. METHODS: A qualitative study was performed to understand the RTW considerations of Belgian breast cancer absentees who had undergone breast cancer surgery in 2006. Twenty-two participants (mean age 46) were included and interviewed between May 2008 and August 2009 in their personal environment. An in-depth analysis (Grounded Theory) took place using the Qualitative Analysis Guide of Leuven (Quagol). RESULTS: Before the actual RTW, breast cancer employees try to build an image of the future resumption of work based on medical grounds and their knowledge of the workplace. Four matters are considered prior to RTW: (i) women want to leave the sick role and wish to keep their job; (ii) they consider whether working is worth the effort; (iii) they reflect on their capability; and (iv) they have doubts about being accepted in the workplace after returning. These inner thoughts are both product and input for the interaction with the social environment. The whole process is coloured by uncertainty and vulnerability. CONCLUSION: Our study demonstrated that mental preparation for RTW is not a linear process of improvement. It shows a detailed picture of four types of considerations made by breast cancer survivors before they actually resume work. Vulnerability appears to be an overarching theme during mental preparation. As the social environment plays an important role, people from that environment must become more aware of their influence on decreasing or increasing a woman's vulnerability while preparing for RTW. ispartof: BMC Public Health vol:12 issue:1 ispartof: location:England status: published

Purpose To uncover the neural substrate of cognitive impairment related to adjuvant chemotherapy, we studied cerebral white matter (WM) integrity before and after chemotherapy by using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment. Patients and Methods Thirty-four young premenopausal women with early-stage breast cancer who were exposed to chemotherapy underwent neuropsychologic testing and DTI before the start of chemotherapy (t1) and 3 to 4 months after treatment (t2). Sixteen patients not exposed to chemotherapy and 19 age-matched healthy controls underwent the same assessment at matched intervals. In all groups, we used paired t tests to study changes in neuropsychologic test scores and whole-brain voxel-based paired t tests to study changes in WM fractional anisotropy (FA; a DTI measure that reflects WM tissue organization), with depression scores and intelligence quotient as included covariates. We correlated changes of neuropsychologic test scores with the mean change of FA for regions that survived the paired t tests in patients treated with chemotherapy. Results In contrast to controls, the chemotherapy-treated group performed significantly worse on attention tests, psychomotor speed, and memory at t2 compared with t1 (P < .05). In the chemotherapy-treated group, we found significant decreases of FA in frontal, parietal, and occipital WM tracts after treatment (familywise error P < .05), whereas for both control groups, FA values were the same between t1 and t2. Furthermore, performance changes in attention and verbal memory correlated with mean regional FA changes in chemotherapy-treated patients (P < .05). Conclusion We report evidence of longitudinal changes in cognitive functioning and cerebral WM integrity after chemotherapy as well as an association between both.

Purpose Most female breast cancer patients are forced to interrupt their professional activities during treatment. Qualitative research was carried out to assess women’s experiences of being work disabled because of breast cancer. Patients and methods In-depth interviews were analyzed to understand patient’s experiences and to gain more insight in their perspectives on living with breast cancer. Results We identified a ‘three-experience model’: (1) disruption , with the feeling of irreparable loss, despair and no hope for the future; (2) episode , an unpleasant and inconvenient period, after which life continues as before; and/or (3) meaningful period , during which new life priorities’ are set. Conclusion The different experiences will require different types of support, especially concerning communication around disability and returning to work. Our findings highlight the need of an individual approach of the management of work disability for breast cancer patients.