Effects of physical exercise during adjuvant chemotherapy for breast cancer on long-term tested and perceived cognition: results of a pragmatic follow-up study.

PURPOSE: Cancer-related cognitive impairment (CRCI) following chemotherapy is commonly reported in breast cancer survivors, even years after treatment. Data from preclinical studies suggest that exercise during chemotherapy may prevent or diminish cognitive problems; however, clinical data are scarce. METHODS: This is a pragmatic follow-up study of two original randomized trials, which compares breast cancer patients randomized to exercise during chemotherapy to non-exercise controls 8.5 years post-treatment. Cognitive outcomes include an online neuropsychological test battery and self-reported cognitive complaints. Cognitive performance was compared to normative data and expressed as age-adjusted z-scores. RESULTS: A total of 143 patients participated in the online cognitive testing. Overall, cognitive performance was mildly impaired on some, but not all, cognitive domains, with no significant differences between groups. Clinically relevant cognitive impairment was present in 25% to 40% of all participants, regardless of study group. We observed no statistically significant effect of exercise, or being physically active during chemotherapy, on long-term cognitive performance or self-reported cognition, except for the task reaction time, which favored the control group (ß = -2.04, 95% confidence interval: -38.48; -2.38). We observed no significant association between self-reported higher physical activity levels during chemotherapy or at follow-up and better cognitive outcomes. CONCLUSION: In this pragmatic follow-up study, exercising and being overall more physically active during or after adjuvant chemotherapy for breast cancer was not associated with better tested or self-reported cognitive functioning, on average, 8.5 years after treatment. Future prospective studies are needed to document the complex relationship between exercise and CRCI in cancer survivors.

Effect of Physical Exercise on MRI-Assessed Brain Perfusion in Chemotherapy-Treated Breast Cancer Patients: A Randomized Controlled Trial.

BACKGROUND: Exercise is a promising intervention to alleviate cognitive problems in breast cancer patients, but studies on mechanisms underlying these effects are lacking. PURPOSE: Investigating whether an exercise intervention can affect cerebral blood flow (CBF) in cognitively impaired breast cancer patients and to determine if CBF changes relate to memory function. STUDY TYPE: Prospective. POPULATION: A total of 181 chemotherapy-treated stage I-III breast cancer patients with cognitive problems and relatively low physical activity levels (≤150 minutes moderate to vigorous physical activity per week), divided into an exercise (N = 91) or control group (N = 90). FIELD STRENGTH/SEQUENCE: Two-dimensional echo planar pseudo-continuous arterial spin labeling CBF sequence at 3 T. ASSESSMENT: The 6-month long intervention consisted of (supervised) aerobic and strength training, 4 × 1 hour/week. Measurements at baseline (2-4 years post-diagnosis) and after 6 months included gray matter CBF in the whole brain, hippocampus, anterior cingulate cortex, and posterior cingulate cortex. Physical fitness and memory function were also assessed. Subgroup analyses were performed in patients with high fatigue levels at baseline. STATISTICAL TESTS: Multiple regression analyses with a two-sided alpha of 0.05 for all analyses. RESULTS: There was a significant improvement in physical fitness (VO2peak in mL/minute/kg) in the intervention group (N = 53) compared to controls (N = 51, ß = 1.47 mL/minute/kg, 95% CI: 0.44-2.50). However, no intervention effects on CBF were found (eg, whole brain: P = 0.565). Highly fatigued patients showed larger but insignificant treatment effects on CBF (eg, whole brain: P = 0.098). Additionally, irrespective of group, a change in physical fitness was positively associated with changes in CBF (eg, whole brain: ß = 0.75, 95% CI: 0.07-1.43). There was no significant relation between CBF changes and changes in memory performance. DATA CONCLUSION: The exercise intervention did not affect CBF of cognitively affected breast cancer patients. A change in physical fitness was associated with changes in CBF, but changes in CBF were not associated with memory functioning. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

Comparison between de novo and metachronous metastatic breast cancer: the presence of a primary tumour is not the only difference-a Dutch population-based study from 2008 to 2018.

PURPOSE: The aim of this study was to compare characteristics and survival of patients with de novo and metachronous metastatic breast cancer. METHODS: Data of patients with metastatic breast cancer were obtained from the Netherlands Cancer Registry. Patients were categorized as having de novo metastatic breast cancer (n = 8656) if they had distant metastases at initial presentation, or metachronous metastatic disease (n = 2374) in case they developed metastases within 5 or 10 years after initial breast cancer diagnosis. Clinicopathological characteristics and treatments of these two groups were compared, after which multiple imputation was performed to account for missing data. Overall survival was compared for patients treated with systemic therapy in the metastatic setting, using Kaplan Meier curves and multivariable Cox proportional hazards models. The hazard ratio for overall survival of de novo versus metachronous metastases was assessed accounting for time-varying effects. RESULTS: Compared to metachronous patients, patients with de novo metastatic breast cancer were more likely to be ≥ 70 years, to have invasive lobular carcinoma, clinical T3 or T4 tumours, loco-regional lymph node metastases, HER2 positivity, bone only disease and to have received systemic therapy in the metastatic setting. They were less likely to have triple negative tumours and liver or brain metastases. Patients with de novo metastases survived longer (median 34.7 months) than patients with metachronous metastases (median 24.3 months) and the hazard ratio (0.75) varied over time. CONCLUSIONS: Differences in clinicopathological characteristics and survival between de novo and metachronous metastatic breast cancer highlight that these are distinct patients groups.

Long-term effects of premenopausal risk-reducing salpingo-oophorectomy on cognition in women with high familial risk of ovarian cancer: A cross-sectional study.

OBJECTIVE: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO. DESIGN: A cross-sectional study with prospective follow-up, nested in a nationwide cohort. SETTING: Multicentre in the Netherlands. POPULATION OR SAMPLE: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment. METHODS: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression. MAIN OUTCOME MEASURES: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO. RESULTS: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years). CONCLUSIONS: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

Mind your words: Oncologists' communication that potentially harms patients with advanced cancer: A survey on patient perspectives.

BACKGROUND: Many complaints in medicine and in advanced illnesses are about communication. Little is known about which specific communications harm. This study explored the perspectives of patients with advanced cancer about potentially harmful communication behaviors by oncologists and helpful alternatives. METHODS: An online survey design was used that was based on literature scoping and patient/clinician/researcher input. Patients with advanced cancer (n = 74) reflected on the potential harmfulness of 19 communication situations. They were asked whether they perceived the situation as one in which communication could be harmful (yes/no). If they answered "yes," they were asked whether they perceived the examples as harmful (yes/no) or helpful (yes/no) and to provide open comments. Results were analyzed quantitatively and qualitatively (content analysis). RESULTS: Communication regarding information provision, prognosis discussion, decision-making, and empathy could be unnecessarily potentially harmful, and this occurred in various ways, such as making vague promises instead of concrete ones (92%), being too directive in decision-making (qualitative), and not listening to the patient (88%). Not all patients considered other situations potentially harmful (eg, introducing the option of refraining from anticancer therapy [49%] and giving too much [prognostic] information [60%]). Exploring each individual patients' needs/preferences seemed to be a precondition for helpful communication. CONCLUSIONS: This article provides patient perspectives on oncologists' unnecessarily potentially harmful communication behaviors and offers practical tools to improve communication in advanced cancer care. Both preventable pitfalls and delicate challenges requiring an individualized approach, where exploration might help, are described. Although providing difficult and unwelcome news is a core task for clinicians, this study might help them to do so while preventing potentially unnecessary harm.

Patient-centered research: how do women tolerate nipple fluid aspiration as a potential screening tool for breast cancer?

BACKGROUND: Nipple fluid aspiration (NFA) is a technique to acquire nipple aspirate fluid (NAF), which is considered a rich source of breast-specific biomarkers. Originating directly from the mammary ducts, this liquid biopsy can offer insight into the process of carcinogenesis at its earliest stage and therefore could be of added value to the current imaging-based breast cancer screening tools. With that in mind, it is necessary to know how well NFA is tolerated. AIM: To evaluate the participants' tolerability of NFA compared to breast imaging screening methods and blood draws. MATERIALS AND METHODS: Three cohorts of women underwent NFA: healthy women (n = 190), women diagnosed with breast cancer (n = 137) and women at high risk of developing breast cancer (n = 48). A 0-10 discomfort score of NFA, mammography, breast MRI and blood draws, was filled in at the study visits, which took place once or annually. RESULTS: The median discomfort rate of NFA was 1, which was significantly lower than the median discomfort of mammography and breast MRI (5 and 3, respectively, p < 0.001), but significantly higher than median discomfort for blood draws (0, p < 0.001). The great majority of women would undergo the procedure again (98%) and recommend it to others (97%). CONCLUSION: This study shows that NFA was well tolerated by healthy women, women diagnosed with breast cancer and high-risk women. This makes NFA a feasible method to pursue as a potential future breast cancer early detection tool, based on resident biomarkers. TRIAL REGISTRATION: NL41845.041.12 , NL57343.041.16 and NL11690.041.06 in trialregister.nl.

Shared decision making in cancer treatment: A Dutch national survey on patients' preferences and perceptions.

OBJECTIVE: Shared decision making (SDM) for cancer treatment yields positive results. However, it appears that discussing essential topics for SDM is not fully integrated into treatment decision making yet. Therefore, we aim to explore to what extent discussion of therapy options, treatment consequences, and personal priorities is preferred and perceived by (former) cancer patients. METHODS: An online questionnaire was distributed by the Dutch Federation of Cancer Patient Organisations among (former) cancer patients in 2018. RESULTS: Among 3785 (former) cancer patients, 3254 patients (86%) had discussed treatments with their health care provider (HCP) and were included for analysis. Mean age was 62.1 ± 11.5; 55% were female. Discussing the option to choose no (further) treatment was rated by 2751 (84.5%) as very important (median score 9/10-IQR 8-10). Its occurrence was perceived by 28% (N = 899), and short- and long-term treatment consequences were discussed in 81% (N = 2626) and 53% (N = 1727), respectively. An unmet wish to discuss short- and long-term consequences was reported by 22% and 26%, respectively. Less than half of the (former) cancer patients perceived that personal priorities (44%) and future plans (34%) were discussed. CONCLUSION: In the perception of (former) cancer patients, several essential elements for effective SDM are insufficiently discussed during cancer treatment decision making.

Concurrent versus sequential use of trastuzumab and chemotherapy in early HER2+ breast cancer.

PURPOSE: The addition of trastuzumab to adjuvant chemotherapy has improved the outcome of human epidermal growth-factor receptor 2 (HER2)-positive breast cancer. Uncertainty remains about the optimal timing of trastuzumab treatment. Therefore, we compared long-term outcome after concurrent versus sequential treatment, in a population-based setting, using data from the nationwide Netherlands Cancer Registry. METHODS: We identified 1843 women diagnosed in The Netherlands from January 1st 2005 until January 1st 2008 with primary, HER2-positive, T1-4NanyM0 breast cancer who received adjuvant chemotherapy and trastuzumab. Kaplan-Meier survival estimates and Cox regression were used to compare recurrence-free survival (RFS) and overall survival (OS) between women who received trastuzumab concurrently with versus sequentially after chemotherapy. Hazard ratios (HR) were adjusted for age, year of diagnosis, grade, pathological T-stage, number of positive lymph nodes, ER-status, PR-status, socio-economic status, radiotherapy, hormonal therapy, ovarian ablation, and type of chemotherapy. RESULTS: After a median follow-up of 8.2 years, RFS events had occurred in 224 out of 1235 (18.1%) concurrently treated women and 129 out of 608 (21.2%) sequentially treated women (adjusted-HR 0.91; 95% confidence interval (CI) 0.67-1.24; P = 0.580). Deaths occurred in 182/1235 (14.7%) concurrently treated women and 104/608 (17.1%) sequentially treated women (adjusted-HR 0.92; 95% CI 0.65-1.29; P = 0.635). CONCLUSIONS: The results of this population-based study are consistent with earlier randomized trials, demonstrating a non-significant difference in outcome for concurrently treated women compared to those who were treated sequentially, suggesting both options are justified.

Patients' preferred and perceived level of involvement in decision making for cancer treatment: A systematic review.

OBJECTIVE: Patient involvement in decision making is conditional for personalised treatment decisions. We aim to provide an up-to-date overview of patients' preferred and perceived level of involvement in decision making for cancer treatment. METHODS: A systematic search was performed in PubMed, EMBASE, PsycINFO and CINAHL for articles published between January 2009 and January 2020. Search terms were 'decision making', 'patient participation', 'oncology', 'perception' and 'treatment'. Inclusion criteria were: written in English, peer-reviewed, reporting patients' preferred and perceived level of involvement, including adult cancer patients and concerning decision making for cancer treatment. The percentages of patients preferring and perceiving an active, shared or passive decision role and the (dis)concordance are presented. Quality assessment was performed with a modified version of the New-Castle Ottawa Scale. RESULTS: 31 studies were included. The median percentage of patients preferring an active, shared or passive role in decision making was respectively 25%, 46%, and 27%. The median percentage of patients perceiving an active, shared or passive role was respectively 27%, 39%, and 34%. The median concordance in preferred and perceived role of all studies was 70%. Disconcordance was highest for a shared role; 42%. CONCLUSIONS: Patients' preferences for involvement in cancer treatment decision vary widely. A significant number of patients perceived a decisional role other than preferred. Improvements in patient involvement have been observed in the last decade. However, there is still room for improvement and physicians should explore patients' preferences for involvement in decision making in order to truly deliver personalised cancer care.

Effects of a time out consultation with the general practitioner on cancer treatment decision-making: a randomised controlled trial: Time out with the general practitioner and cancer treatment decision.

OBJECTIVE: Improving shared decision-making (SDM) enables more tailored cancer treatment decisions. We evaluated a Time Out consultation (TOC) with the general practitioner (GP), between cancer diagnosis and treatment decision, which aims at supporting SDM and improving continuity of primary care. This study aims to evaluate the effects of a TOC on perceived SDM, information provision and self-efficacy. METHODS: This randomised controlled trial included newly diagnosed patients with curable cancer (breast, lung, colorectal, gynaecologic and melanoma) from four Dutch hospitals. Primary outcome is perceived SDM and secondary outcomes are information provision and self-efficacy. RESULTS: One hundred fifty-four patients (control n = 77, intervention n = 77) - female: 75%, mean age: 61 (SD ± 11.9). In the intervention group, 80.5% (n = 62) had a TOC, of which 82.3% (n = 51) took place after treatment decision. Perceived SDM was lower in the intervention group (-8.9 [95% CI: 0.6-17.1]). Among those with a TOC before treatment decision (n = 11), perceived SDM was comparable to the control group (66.5 ± 27.2 vs. 67.9 ± 26.1). CONCLUSION: Even though patients are motivated to have a TOC, implementing a TOC between diagnosis and treatment decision is challenging. Effects of a timely TOC could not be established. Non-timely TOC decreased perceived SDM. Planning of the TOC should be optimised, and future research should establish if adequately timed TOC results in improved SDM in cancer patients.

Treatment decision-making and the added value of the general practitioner: A qualitative exploration of cancer patients' perspectives.

OBJECTIVE: Cancer patients are increasingly involved in decision-making for cancer treatment. General practitioners' (GPs) support in this process is advocated. Therefore, GPs need to be aware of patients' treatment decision-making process and their potential role. We aim to understand the treatment decision-making process and to explore the added value of GP involvement, from the perspective of cancer patients treated with curative intent. METHODS: An explorative qualitative study was performed. Semi-structured interviews were conducted with 20 purposively sampled Dutch cancer patients treated with curative intent. RESULTS: Patients' treatment decision-making process was dominated by a focus on 'safeguarding survival'. Patients generally followed the treatment plan as proposed by their physician and did not always experience having a treatment choice. The majority of patients expressed added value for GP involvement, mainly to provide psychological support, but also for providing shared decision-making (SDM) support. CONCLUSION: The treatment decision-making process of cancer patients treated with curative intent is dominated by the urge to 'safeguard survival'. GPs should be aware of their added value in providing psychological support and their potential role to support SDM following a cancer diagnosis.

Addressing challenges in information-provision: a qualitative study among oncologists and women with advanced breast cancer.

BACKGROUND: There is a need for more insight into how to address challenges of information-provision for women with advanced breast cancer. We aimed to explore oncologists' and patients' views on (i) the challenges of information-provision, and (ii) possible strategies to address these challenges, meanwhile (iii) exploring the possible facilitating role of positive expectations and empathy. METHODS: Semi-structured interviews were held with oncologists (n = 10) and women with advanced breast cancer (n = 14). Principles of Thematic Analysis were followed, with two researchers analyzing transcribed data, supported by Atlas.ti software. RESULTS: Taken together the data from oncologists and patients, we found that when communicating with patients with advanced cancer, oncologists face challenges, including handling patients' unrealistic disease (status) beliefs, and choosing approaches for discussing available treatment options and their side effects. Possible strategies to address these challenges include balancing information with acceptance of denial, and using medical expertise to guide treatment discussions. A sensitive issue is whether to discuss the option of no anti-cancer treatment. Meanwhile, approaches and preferences for discussions of side effects vary. Positive expectations and empathy can facilitate information-provision by creating space and helping patients to open up more. CONCLUSIONS: Integrating oncologists' and patients' views, oncologists can provide realistic information while also, temporarily, accepting denial, and can use their medical expertise to address challenges around unrealistic beliefs and discussion of treatment options. Finding ways to tailor discussions of no anti-cancer treatment and side-effect information are needed. Positive expectations and empathy might facilitate - tailored - information-provision, leading ultimately to patient-centered care lying at the heart of medicine.

Significant inter- and intra-laboratory variation in grading of invasive breast cancer: A nationwide study of 33,043 patients in the Netherlands.

Accurate, consistent and reproducible grading by pathologists is of key-importance for identification of individual patients with invasive breast cancer (IBC) that will or will not benefit from adjuvant systemic treatment. We studied the laboratory-specific grading variation using nationwide real-life data to create insight and awareness in grading variation. Synoptic pathology reports of all IBC resection-specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch Pathology Registry (PALGA). Absolute differences in laboratory-proportions of Grades I-III were compared to the national reference. Multivariable logistic regression provided laboratory-specific odds ratios (ORs) for high- vs. low-grade IBC. 33,792 IBC pathology reports of 33,043 patients from 39 laboratories were included, of which 28.1% were reported as Grade I (range between laboratories 16.3-43.3%), 47.6% as Grade II (38.4-57.8%), and 24.3% as Grade III (15.5-34.3%). Based on national guidelines, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. After case-mix correction, 20 laboratories (51.3%) showed a significantly deviant OR. Significant grading differences were also observed among pathologists within laboratories. In this cohort of 33,043 breast cancer patients, we observed substantial inter- and intra-laboratory variation in histologic grading. It can be anticipated that this has influenced outcome including exposure to unnecessary toxicity, since choice of adjuvant chemotherapy was dependent on grade in nearly a third of patients. Better standardization and training seems warranted.

The effect of an e-learning module on grading variation of (pre)malignant breast lesions.

Histologic grade is a biomarker that is widely used to guide treatment of invasive breast cancer (IBC) and ductal carcinoma in situ of the breast (DCIS). Yet, currently, substantial grading variation between laboratories and pathologists exists in daily pathology practice. This study was conducted to evaluate whether an e-learning may be a feasible tool to decrease grading variation of (pre)malignant breast lesions. An e-learning module, representing the key-concepts of grading (pre)malignant breast lesions through gold standard digital images, was designed. Pathologists and residents could take part in either or both the separate modules on DCIS and IBC. Variation in grading of a digital set of lesions before and after the e-learning was compared in a fully-crossed study-design. Multiple outcome measures were assessed: inter-rater reliability (IRR) by Light's kappa, the number of images graded unanimously, the number of images with both extreme scores (i.e., grade I and grade III), and the average number of discrepancies from expert-consensus. Participants were included as they completed both the pre- and post-e-learning set (DCIS-module: n = 36, IBC-module: n = 21). For DCIS, all outcome measures improved after e-learning, with the IRR improving from fair (kappa: 0.532) to good (kappa: 0.657). For IBC, all outcome measures for the subcategories tubular differentiation and mitosis improved, with >90% of participants agreeing on almost 90% of the images after the e-learning. In contrast, the IRR for the subcategory of nuclear pleomorphism remained fair (kappa: 0.523 vs. kappa: 0.571). This study shows that an e-learning module, in which pathologists and residents are trained in histologic grading of DCIS and IBC, is a feasible and promising tool to decrease grading variation of (pre)malignant breast lesions. This is highly relevant given the important role of histologic grading in clinical decision making of (pre)malignant breast lesions.

The Physiological MicroRNA Landscape in Nipple Aspirate Fluid: Differences and Similarities with Breast Tissue, Breast Milk, Plasma and Serum.

BACKGROUND: MicroRNAs (miRNAs) target 60% of human messenger RNAs and can be detected in tissues and biofluids without loss of stability during sample processing, making them highly appraised upcoming biomarkers for evaluation of disease. However, reporting of the abundantly expressed miRNAs in healthy samples is often surpassed. Here, we characterized for the first time the physiological miRNA landscape in a biofluid of the healthy breast: nipple aspirate fluid (NAF), and compared NAF miRNA expression patterns with publically available miRNA expression profiles of healthy breast tissue, breast milk, plasma and serum. METHODS: MiRNA RT-qPCR profiling of NAF (n = 41) and serum (n = 23) samples from two healthy female cohorts was performed using the TaqMan OpenArray Human Advanced MicroRNA 754-Panel. MiRNA quantification data based on non-targeted or multi-targeted profiling techniques for breast tissue, breast milk, plasma and serum were retrieved from the literature by means of a systematic search. MiRNAs from each individual study were orderly ranked between 1 and 50, combined into an overall ranking per sample type and compared. RESULTS: NAF expressed 11 unique miRNAs and shared 21/50 miRNAs with breast tissue. Seven miRNAs were shared between the five sample types. Overlap between sample types varied between 42% and 62%. Highly ranked NAF miRNAs have established roles in breast carcinogenesis. CONCLUSION: This is the first study to characterize and compare the unique physiological NAF-derived miRNA landscape with the physiological expression pattern in breast tissue, breast milk, plasma and serum. Breast-specific sources did not mutually overlap more than with systemic sources. Given their established role in carcinogenesis, NAF miRNA assessment could be a valuable tool in breast tumor diagnostics.

Hormone- and HER2-receptor assessment in 33,046 breast cancer patients: a nationwide comparison of positivity rates between pathology laboratories in the Netherlands.

PURPOSE: Patient management of invasive breast cancer (IBC) is to a large extent based on hormone- and HER2-receptor assessment. High-quality, reliable receptor assessment is of key importance as false results may lead to under- or overtreatment of patients. Surveillance of case-mix adjusted positivity rates has been suggested as a tool to identify laboratories with insufficient testing assays, as this covers the whole process of receptor assessment and enables laboratories to benchmark their positivity rates against other laboratories. We studied laboratory-specific variation in hormone- and HER2 positivity rates of 33,046 breast cancer patients using real-life nationwide data. METHODS: All synoptic pathology reports of IBC resection-specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch pathology registry (PALGA). Absolute and case-mix adjusted receptor positivity rates were compared to the mean national proportion and presented in funnel plots in separate analyses for estrogen (ER), progesterone (PR) and HER2. Case-mix adjustment was performed by multivariable logistic regression. RESULTS: 33,794 IBC lesions from 33,046 patients of 39 pathology laboratories were included. After case-mix adjustment, mean positivity rates were 87.2% for ER (range 80.4-94.3), 71.3% for PR (62.5-77.5%), and 9.9% for HER2 (5.5-12.7%). Overall, 14 (35.9%), 17 (43.6%) and 11 (28.2%) laboratories showed positivity rates outside the 95% confidence interval for ER, PR and HER2, respectively. CONCLUSION: This nationwide study shows that absolute variation in hormone- and HER2-receptor positivity rates between Dutch pathology laboratories is limited. Yet, the considerable number of outlying laboratories shows that there is still need for improvement. Continuous monitoring and benchmarking of positivity rates may help to realize this.

Application of Nipple Aspirate Fluid miRNA Profiles for Early Breast Cancer Detection and Management.

The authors of the recently published review, "Why the Gold Standard Approach by Mammography Demands Extension by Multiomics [...].

Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy.

PURPOSE: Exercise has been shown to reduce fatigue during cancer treatment. Hypothesized mechanisms include inflammatory pathways. Therefore, we investigated effects of exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy. METHODS: We pooled data from two randomized controlled exercise intervention trials with breast cancer patients during adjuvant chemotherapy (n = 130), which had previously shown beneficial effects of exercise on fatigue. Exercise comprised a 12-week resistance training (BEATE study) or an 18-week combined resistance and aerobic training (PACT study). Serum IL-6, IL-1ra, and the IL-6/IL-1ra ratio were quantified at baseline, mid-intervention, post-intervention, and 6-9 months post-baseline. RESULTS: Mixed effect models showed significant increases in IL-6 and IL-6/IL-1ra ratio during chemotherapy and decreases afterwards. Differences between exercise and control group were not significant at any time point. Changes in total cancer-related fatigue were significantly correlated with changes in IL-6/IL-1ra ratio (partial correlation r = 0.23) and IL-6 (r = 0.21), and changes in physical cancer-related fatigue with changes in IL-6/IL-1ra ratio (r = 0.21). CONCLUSIONS: Changes in fatigue were slightly correlated with changes in inflammatory markers, and there was a strong inflammatory response to adjuvant chemotherapy. The supervised exercise training did not counteract this increase in inflammation, suggesting that beneficial effects of exercise on fatigue during adjuvant chemotherapy for breast cancer are not essentially mediated by IL-6, IL-1ra, or the IL-6/IL-1ra ratio.

Four-year effects of exercise on fatigue and physical activity in patients with cancer.

BACKGROUND: In the earlier randomized controlled Physical Activity during Cancer Treatment (PACT) study, we found beneficial effects of an 18-week supervised exercise program on fatigue in patients with newly diagnosed breast or colon cancer undergoing adjuvant treatment. The present study assessed long-term effects of the exercise program on levels of fatigue and physical activity 4 years after participation in the PACT study. METHODS: The original study was a two-armed, multicenter randomized controlled trial comparing an 18-week supervised exercise program to usual care among 204 breast cancer patients and 33 colon cancer patients undergoing adjuvant treatment. Of the 237 PACT participants, 197 participants were eligible and approached to participate in the 4-year post-baseline measurements, and 128 patients responded. We assessed fatigue and physical activity levels at 4 years post-baseline and compared this to levels at baseline, post-intervention (18 weeks post-baseline), and at 36 weeks post-baseline. RESULTS: Intention-to-treat mixed linear effects model analyses showed that cancer patients in the intervention group reported significantly higher moderate-to-vigorous total physical activity levels (141.46 min/week (95% confidence interval (CI) 1.31, 281.61, effect size (ES) = 0.22) after 4 years compared to the usual care group. Furthermore, cancer patients in the intervention group tended to experience less physical fatigue at 4 years post-baseline compared to the usual care group (- 1.13, 95% CI -2.45, 0.20, ES = 0.22), although the result was not statistically significant. CONCLUSION: Patients with breast or colon cancer who participated in the 18-week exercise intervention showed significant higher levels of moderate-to-vigorous total physical activity levels and a tendency towards lower physical fatigue levels 4 years post-baseline. Our result indicate that exercising during chemotherapy is a promising strategy for minimizing treatment-related side effects, both short and long term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571 , Dutch Trial Register NTR2138 . Trial registered on 9 December 2009.

p120-Catenin Is Critical for the Development of Invasive Lobular Carcinoma in Mice.

Loss of E-cadherin expression is causal to the development of invasive lobular breast carcinoma (ILC). E-cadherin loss leads to dismantling of the adherens junction and subsequent translocation of p120-catenin (p120) to the cytosol and nucleus. Although p120 is critical for the metastatic potential of ILC through the regulation of Rock-dependent anoikis resistance, it remains unknown whether p120 also contributes to ILC development. Using genetically engineered mouse models with mammary gland-specific inactivation of E-cadherin, p120 and p53, we demonstrate that ILC formation induced by E-cadherin and p53 loss is severely impaired upon concomitant inactivation of p120. Tumors that developed in the triple-knockout mice were mostly basal sarcomatoid carcinomas that displayed overt nuclear atypia and multinucleation. In line with the strong reduction in ILC incidence in triple-knockout mice compared to E-cadherin and p53 double-knockout mice, no functional redundancy of p120 family members was observed in mouse ILC development, as expression and localization of ARVCF, p0071 or δ-catenin was unaltered in ILCs from triple-knockout mice. In conclusion, we show that loss of p120 in the context of the p53-deficient mouse models is dominant over E-cadherin inactivation and its inactivation promotes the development of basal, epithelial-to-mesenchymal-transition (EMT)-type invasive mammary tumors.