Effect of myofascial techniques for treatment of persistent arm pain after breast cancer treatment: randomized controlled trial.

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/cm2) and pain quality (McGill Pain Questionnaire). Measures were taken before and after the intervention and at long term (6 and 12 months 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 12 months either.

Effect of myofascial techniques for treatment of upper limb dysfunctions in breast cancer survivors: randomized controlled trial.

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.

Myofascial techniques have no additional beneficial effects to a standard physical therapy programme for upper limb pain after breast cancer surgery: a randomized controlled trial.

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/cm2)) and pain quality (McGill Pain Questionnaire) were evaluated. All measurements were performed at 2 (=baseline), 4, 9 and 12 months post-surgery. RESULTS: At 4, 9 and 12 months 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/cm2, 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/cm2, 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.

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Effectiveness of postoperative physical therapy for upper-limb impairments after breast cancer treatment: a systematic review.

OBJECTIVE: To systematically review the effectiveness of various postoperative physical therapy modalities and timing of physical therapy after treatment of breast cancer on pain and impaired range of motion (ROM) of the upper limb. DATA SOURCES: We searched the following databases: PubMed/MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, Physiotherapy Evidence Database, and Cochrane. Articles published until October 2012 were included. STUDY SELECTION: Only (pseudo) randomized controlled trials and nonrandomized experimental trials investigating the effectiveness of passive mobilization, manual stretching, myofascial therapy, and/or exercise therapy and timing of physical therapy after treatment for breast cancer are reviewed. Primary outcomes are pain of the upper limb and/or ROM of the shoulder. Secondary outcomes are decreased shoulder strength, arm lymphedema, limitations in activities of daily living, decreased quality of life, and wound drainage volume. Physical therapy modalities had to be started in the first 6 weeks after surgery. DATA EXTRACTION: Articles were selected by 2 independent researchers in 3 phases and compared for consensus. First the titles were analyzed, and then the selected abstracts and finally the full texts were reviewed. DATA SYNTHESIS: Eighteen randomized controlled trials were included in the review. Three studies investigated the effect of multifactorial therapy: 2 studies confirmed that the combination of general exercises and stretching is effective for the treatment of impaired ROM another study showed that passive mobilization combined with massage had no beneficial effects on pain and impaired ROM. Fifteen studies investigated the effectiveness of a single physical therapy modality. One study of poor quality found evidence supporting the beneficial effects of passive mobilization. The only study investigating the effect of stretching did not find any beneficial effects. No studies were found about the effectiveness of myofascial therapy in the postoperative phase. Five studies found that active exercises were more effective than no therapy or information on the treatment of impairments of the upper limb. Three studies supported the early start of exercises for recovery of shoulder ROM, whereas 4 studies supported the delay of exercises to avoid prolonged wound healing. CONCLUSIONS: Multifactorial physical therapy (ie, stretching, exercises) and active exercises were effective to treat postoperative pain and impaired ROM after treatment for breast cancer. High-quality studies are necessary to determine the effectiveness of passive mobilization, stretching, and myofascial therapy as part of the multifactorial treatment. In addition, the appropriate timing and content of the exercise programs need to be further investigated.

Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial.

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: <50 years 1·09 [95% CI 0·79-1·51] vs ≥50 years 1·16 [0·90-1·50]; overall survival <50 years 1·17 [0·86-1·59] 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).

Vitamin D status at breast cancer diagnosis: correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency.

We correlated serum 25-hydroxyvitamin D(3) (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.

Survived but feeling vulnerable and insecure: a qualitative study of the mental preparation for RTW after breast cancer treatment.

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.

Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients.

A subgroup of patients with breast cancer suffers from mild cognitive impairment after chemotherapy. To uncover the neural substrate of these mental complaints, we examined cerebral white matter (WM) integrity after chemotherapy using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment. Postchemotherapy breast cancer patients (n = 17) and matched healthy controls (n = 18) were recruited for DTI and neuropsychological testing, including the self-report cognitive failure questionnaire (CFQ). Differences in DTI WM integrity parameters [fractional anisotropy (FA) and mean diffusivity (MD)] between patients and healthy controls were assessed using a voxel-based two-sample-t-test. In comparison with healthy controls, the patient group demonstrated decreased FA in frontal and temporal WM tracts and increased MD in frontal WM. These differences were also confirmed when comparing this patient group with an additional control group of nonchemotherapy-treated breast cancer patients (n = 10). To address the heterogeneity observed in cognitive function after chemotherapy, we performed a voxel-based correlation analysis between FA values and individual neuropsychological test scores. Significant correlations of FA with neuropsychological tests covering the domain of attention and processing/psychomotor speed were found in temporal and parietal WM tracts. Furthermore, CFQ scores correlated negatively in frontal and parietal WM. These studies show that chemotherapy seems to affect WM integrity and that parameters derived from DTI have the required sensitivity to quantify neural changes related to chemotherapy-induced mild cognitive impairment.

Physical activity levels after treatment for breast cancer: one-year follow-up.

Among patients with breast cancer, few studies have examined the pattern of change of physical activity levels over time or the predictive factors for this change. Particularly sparse are studies comparing pre-surgical physical activity levels with those 12 months post-surgery. Patients with a primary operable breast cancer (N = 267) filled in the Physical Activity Computerised Questionnaire before breast surgery and 1, 3, 6 and 12 months post-operatively. Patient-, disease- and treatment-related factors were prospectively collected. Total physical activity level and occupational, sport and household activity levels were significantly decreased the first month post-operatively and did not recover during the first year after surgery. 'Being employed' was a predictive factor for a larger decrease of the total activity level, comparing the pre-operative and 12 months post-surgery stages. Having a spouse, a pN2-3 lesion and over 20 lymph nodes dissected predicted a decrease in occupational activity. Advanced age and smoking behaviour predicted a decrease in sport activities, and not having a spouse predicted a decrease in household activities. This study showed that 1 year after breast cancer surgery, pre-operative physical activity levels were not recovered. Breast cancer patients, and in particular those at risk for a decreased physical activity level, should be identified, encouraged and guided to increase their activities.

Experiences and concerns about 'returning to work' for women breast cancer survivors: a literature review.

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.

Additional value of PET-CT in staging of clinical stage IIB and III 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.

Lifestyle changes and breast cancer prognosis: a review.

OBJECTIVE: Because of its high incidence and improving survival, breast cancer is currently the most prevalent cancer in the world. We reviewed the published literature in our search for modifiable factors valuable as an adjuvant health measure to surgery, radio and systemic therapy for breast cancer. METHODS: We included material which was identified from computerised searches of PubMed (1966 to May, 2007). Published material was restricted to prospective cohort studies and randomised clinical trials. We reviewed the literature concerning the association between physical activity, smoking, weight gain after the diagnosis, diet and prognosis. RESULTS AND CONCLUSION: We conclude that life style changes following standard breast cancer therapy are highly recommended (although scientific evidence is still lacking for some of inconsistency regarding available data). They include physical activity, weight control, high consumption of fruit and vegetables, and a reduction of dietary fat intake.

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant.

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.

Axillary lymph node status of operable breast cancers by combined steroid receptor and HER-2 status: triple positive tumours are more likely lymph node positive.

AIMS: To examine the frequency of axillary lymph node (ALN) invasion of operable breast cancers by their combined oestrogen receptor (ER), progesterone receptor (PR) and HER-2 status. METHODS: 2227 recently operated cases in one centre were retrieved from the Multidisciplinary Breast Centre database and stratified according to their combined immunohistochemical (IHC) expression of ER/PR/HER-2 status. An equivocal HER-2 status was further analysed by Fluorescence in situ Hybridisation (FISH). The following 6 groups were considered: ER(-)PR(-)HER-2(-) (NNN; triple negative), ER(-)PR(-)HER-2(+) (NNP), ER(+)PR(-)HER-2(-) (PNN), ER(+)PR(-)HER-2(+) (PNP), ER(+)PR(+)HER-2(- )(PPN), ER(+)PR(+)HER-2(+) (PPP; triple positive). For ALN, the following variables were tested in uni- and multivariate models: age at diagnosis (years), tumour size (mm), tumour grade, ER, PR, HER-2 and the combined steroid receptor and HER-2 status. Likelihood ratio chi(2)-tests were used for univariate analysis and logistic regression for multivariate analysis. RESULTS: Triple positive tumours had a higher likelihood of being ALN positive than others (56.2% versus 35.7%; P<0.0001). Univariate logistic regression also withheld age, size, grade and HER-2 as predictors of ALN involvement. Final multivariate logistic regression revealed age, size, grade and PPP versus non-PPP to be independent predictors of ALN involvement; the odds ratio (OR) and 95% CI for PPP versus non-PPP tumours was 2.169 (1.490-3.156). CONCLUSION: Our data provide insight into the natural history of triple positive breast carcinomas. Such tumours are more likely ALN positive than those with another steroid receptor and HER-2 status. How these findings correlate with breast cancer prognosis remains to be investigated.

Short-term outcome of primary operated early breast cancer by hormone and HER-2 receptors.

INTRODUCTION: Prognostic subgroup classification of operable breast cancers using cDNA clustering of breast cancer-related genes resembles the classification based on the combined immunohistochemical (IHC) expression of the hormone and HER-2 receptors. We here report the short-term disease-free interval (DFI) of operable breast cancers by their joint hormone receptor/HER-2 phenotype. PATIENTS AND METHODS: Short-term follow-up (FU) of a prospective cohort of 1,958 breast-cancer patients primary operated at our institution between 2000 and 2005. Receptors were evaluated using IHC. Steroid receptors were considered positive for any nuclear staining; HER-2 for strong (3+) membrane staining or positive fluorescence in situ hybridization (FISH). Kaplan-Meier (KM) DFI curves were calculated for any relapse defined as a local, regional, contralateral, or distant breast cancer event for the six predefined breast cancer subgroups: ER + PR + HER-2 - (PPN), ER + PR - HER-2 - (PNN), ER + PR + HER-2 + (PPP), ER - PR - HER-2 - (NNN), ER - PR - HER-2 + (NNP), and ER + PR - HER-2 + (PNP). P-values were calculated for comparison of the six different survival curves using two possible adaptations for multiple testing. A multivariate model for the receptors predicting DFI did incorporate local and systemic adjuvant therapy. RESULTS: Median patient age was 57 years (ranges 26-96) and median FU was 3.35 years. Overall, DFI at median FU was 91%; 94% for PPN, 89% for PNN, 86% for NNN, 81% for PPP, 80% for PNP, and 76% for NNP cases. Some receptor subgroups had a significantly better DFI than others based on multiple testing, especially when the PPN group was compared against the four most frequent subtypes. The multivariate model with local and systemic adjuvant therapy confirmed the prognostic value of ER, PR, and HER-2 for short-term DFI. CONCLUSION: It is possible to distinguish short-term prognostic breast cancer subgroups only on the basis of ER, PR, and HER-2 even when stratified for local and systemic adjuvant therapy. While gene expression profiles based on microarray data of over hundreds of genes will probably teach us much about breast cancer biology, heterogeneity, and prognosis, we emphasize the important short-term prognostic value of currently used IHC markers for ER, PR, and HER-2.

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 D(3), 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.

Stromal characteristics are adequate prognosticators for recurrence risk in ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast constitutes a heterogeneous group of non-obligate precursors for invasive breast cancer. To date, adequate risk stratification is lacking, which is presumed to result in overtreatment. We previously identified myxoid stromal architecture as a potential prognosticator for loco-regional recurrence. In the present study, we investigated the prognostic potential of stromal characteristics. METHODS: Hematoxylin and eosin stained slides from 211 DCIS patients were reviewed. The following histological features were dichotomously assessed: nuclear grade, DCIS architecture, presence of necrosis, intraductal calcifications, stromal inflammation and myxoid stromal architecture. Loco-regional recurrences constituted the primary endpoint. RESULTS: Cox regression analysis showed that high nuclear grade, myxoid stromal architecture and moderate to extensive stromal inflammation were significantly associated with decreased recurrence-free survival, independent of radiotherapy. Based on these features, a combined risk score (CRS) was calculated, ranging from zero to three. A high CRS of three was associated with significantly shorter recurrence-free survival. Nineteen patients had a CRS of three, of which three relapsed (15.7%), whereas only one out of 113 patients with a CRS of zero relapsed (0.9%). CONCLUSIONS: We were able to validate our previously reported findings regarding the prognostic potential of myxoid periductal stroma in an independent DCIS patient cohort. A CRS based on nuclear grade, myxoid stromal architecture and stromal inflammation might facilitate discrimination of low risk from high risk patients. Consequently, the CRS may tailor adjuvant therapy. Future research should investigate whether radiotherapy can be safely omitted in patients with a low CRS.

Plasma MMP1 and MMP8 expression in breast cancer: protective role of MMP8 against lymph node metastasis.

BACKGROUND: Elevated levels of matrix metalloproteinases have been found to associate with poor prognosis in various carcinomas. This study aimed at evaluating plasma levels of MMP1, MMP8 and MMP13 as diagnostic and prognostic markers of breast cancer. METHODS: A total of 208 breast cancer patients, of which 21 with inflammatory breast cancer, and 42 healthy controls were included. Plasma MMP1, MMP8 and MMP13 levels were measured using ELISA and correlated with clinicopathological characteristics. RESULTS: Median plasma MMP1 levels were higher in controls than in breast cancer patients (3.45 vs. 2.01 ng/ml), while no difference was found for MMP8 (10.74 vs. 10.49 ng/ml). ROC analysis for MMP1 revealed an AUC of 0.67, sensitivity of 80% and specificity of 24% at a cut-off value of 4.24 ng/ml. Plasma MMP13 expression could not be detected. No correlation was found between MMP1 and MMP8 levels. We found a trend of lower MMP1 levels with increasing tumour size (p = 0.07); and higher MMP8 levels with premenopausal status (p = 0.06) and NPI (p = 0.04). The median plasma MMP1 (p = 0.02) and MMP8 (p = 0.007) levels in the non-inflammatory breast cancer patients were almost twice as high as those found in the inflammatory breast cancer patients. Intriguingly, plasma MMP8 levels were positively associated with lymph node involvement but showed a negative correlation with the risk of distant metastasis. Both controls and lymph node negative patients (pN0) had lower MMP8 levels than patients with moderate lymph node involvement (pN1, pN2) (p = 0.001); and showed a trend for higher MMP8 levels compared to patients with extensive lymph node involvement (pN3) and a strong predisposition to distant metastasis (p = 0.11). Based on the hypothesis that blood and tissue protein levels are in reverse association, these results suggest that MMP8 in the tumour may have a protective effect against lymph node metastasis. CONCLUSION: In summary, we observed differences in MMP1 and MMP8 plasma levels between healthy controls and breast cancer patients as well as between breast cancer patients. Interestingly, our results suggest that MMP8 may affect the metastatic behaviour of breast cancer cells through protection against lymph node metastasis, underlining the importance of anti-target identification in drug development.

Manual lymph drainage may not have a preventive effect on the development of breast cancer-related lymphoedema in the long term: a randomised trial.

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 (≥200ml,≥2cm,≥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≥200ml 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≥2cm 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].