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.

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].

An evaluation tool for Myofascial Adhesions in Patients after Breast Cancer (MAP-BC evaluation tool): Concurrent, face and content validity.

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.

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.

An evaluation tool for myofascial adhesions in patients after breast cancer (MAP-BC evaluation tool): Development and interrater reliability.

PURPOSE: To develop a tool to evaluate myofascial adhesions objectively in patients with breast cancer and to investigate its interrater reliability. METHODS: 1) Development of the evaluation tool. Literature was searched, experts in the field of myofascial therapy were consulted and pilot testing was performed. 2) Thirty patients (63% had a mastectomy, 37% breast-conserving surgery and 97% radiotherapy) with myofascial adhesions were evaluated using the developed tool by 2 independent raters. The Weighted Kappa (WK) and the intra-class correlation coefficient (ICC) were calculated. RESULTS: 1) The evaluation tool for Myofascial Adhesions in Patients with Breast Cancer (MAP-BC evaluation tool) consisted of the assessment of myofascial adhesions at 7 locations: axillary and breast region scars, musculi pectorales region, axilla, frontal chest wall, lateral chest wall and the inframammary fold. At each location the degree of the myofascial adhesion was scored at three levels (skin, superficial and deep) on a 4-points scale (between no adhesions and very stiff adhesions). Additionally, a total score (0-9) was calculated, i.e. the sum of the different levels of each location. 2) Interrater agreement of the different levels separately was moderate for the axillary and mastectomy scar (WK 0.62-0.73) and good for the scar on the breast (WK >0.75). Moderate agreement was reached for almost all levels of the non-scar locations. Interrater reliability of the total scores was the highest for the scars (ICC 0.82-0.99). At non-scar locations good interrater reliability was reached, except for the inframammary fold (ICC = 0.71). CONCLUSIONS: The total scores of all locations of the MAP-BC evaluation tool had good to excellent interrater reliability, except for the inframammary fold which only reached moderate reliability.

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.

Pain characteristics as important contributing factors to upper limb dysfunctions in breast cancer survivors at long term.

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.

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.

Arm lymphoedema and upper limb impairments in sentinel node-negative breast cancer patients: A one year follow-up study.

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.

Prognostic features of breast cancer differ between women in the Democratic Republic of Congo and Belgium.

OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: After adjusting for age, tumor volume and tumor grade, ER was more frequently negative (RR = 0.71, p < 0.001), 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). CONCLUSION: 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.

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.

Arthralgia induced by endocrine treatment for breast cancer: A prospective study of serum levels of insulin like growth factor-I, its binding protein and oestrogens.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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 (p<0.0004). 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). CONCLUSION: These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the growth hormone (GH)/IGF-I axis.

Reproducibility of lymphoscintigraphic evaluation of the upper limb.

BACKGROUND: Although reproducibility studies are missing, a lymphoscintigraphic evaluation of the upper limb is often used in routine practice to diagnose lymphedema and in clinical research, for example, to investigate the effect of a physical treatment. Therefore, the aim of the present study was to investigate the reproducibility of the lymphoscintigraphic evaluation of the upper limb. METHODS AND RESULTS: In breast cancer patients, 20 lymphoscintigraphic evaluations of the upper limb were performed on two test occasions with an interval of 1 week. (99m)Tc nanocol was injected subcutaneously in the hand. A standardized protocol was applied. In the early phase, two static images of the injection places were taken and in between dynamic images of both axilla during 40 min (15 min rest, 15 min squeezing a ball, and 15 min rest). After a break of 70 min, a static image of the injection places and of the axilla was made. At the end, a partial whole body image was acquired. A strong reproducibility was found for the following quantitative variables (ICC 0.75 to 0.85): change of uptake in axilla during the break; change of extraction from hands during the break; and extraction and uptake in the late phase. The other quantitative variables (i.e., extraction form the hands in the early phase, time of arrival, accumulation rate, and uptake in axilla in the early phase) had weak to moderatie reproducibility (ICC 0.07 to 0.70). All qualitative variables (i.e., number of lymph nodes in the axilla, upper arm and elbow/lower arm, gradation of lymph collectors in upper or lower arm and of dermal backflow, and presence of lymph collaterals) had strong to very strong reproducibility (ICC 0.76 to 1.00). CONCLUSION: A lymphoscintigraphy of the upper limb is a reproducible imaging tool to assess lymph transport quantitatively and qualitatively.

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.

Longitudinal assessment of chemotherapy-induced alterations in brain activation during multitasking and its relation with cognitive complaints.

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.

Prediction of non-sentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node.

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.

Postoperative evolution of thickness and echogenicity of cutis and subcutis of patients with and without breast cancer-related lymphedema.

BACKGROUND: 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. METHODS AND RESULTS: 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%). CONCLUSION: 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.

Impact of tumor chronology and tumor biology on lymph node metastasis in breast cancer.

SYNOPSIS: The significance of nodal metastasis in breast cancer is under discussion. We investigated the impact of variables of tumor chronology and tumor biology on the presence of lymph node metastases. PURPOSE: Lymph node involvement is the main prognostic factor in breast cancer. However, it is under discussion whether nodal metastasis in breast cancer only reflects the chronological age of the tumor or whether it is also a marker of tumor biology. The goal of our study was to investigate the impact of variables of tumor chronology and biology on the presence of lymph node metastases. METHODS: We performed a retrospective analysis of data from 3002 patients with an early invasive breast carcinoma. All patients underwent primary surgery at the University Hospitals Leuven between 2001 and 2009. First, the impact of tumor size on the presence of lymph node metastasis was evaluated as the chronological age of a tumor is supposed to be reflected in its size. Next, the impact of tumor grade, lymphovascular invasion and the hormone receptor status, which are all variables of tumor biology, was studied. Logistic regression analyses were performed and the area under the ROC curve (AUC) was calculated as a measure of discrimination between logistic regression models. RESULTS: Using pathological tumor size the AUC of prediction was 0.67. Based on variables of tumor biology, axillary lymph node positivity could be predicted with an AUC of 0.68. Combining variables of tumor chronology and biology an AUC of 0.74 for the prediction of axillary lymph node (ALN) positivity was calculated. CONCLUSIONS: According to our data variables of tumor chronology and tumor biology have a similar impact on the presence of lymph node metastasis.

Is the sentinel lymph node biopsy more sensitive for the identification of positive lymph nodes in breast cancer than the axillary lymph node dissection?

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.

Triple negative breast cancer: clinical characteristics in the different histological subtypes.

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.