Reporting on patient's body mass index (BMI) in recent clinical trials for patients with breast cancer: a systematic review.

BACKGROUND: The proportion of patients with breast cancer and obesity is increasing. While the therapeutic landscape of breast cancer has been expanding, we lack knowledge about the potential differential efficacy of most drugs according to the body mass index (BMI). Here, we conducted a systematic review on recent clinical drug trials to document the dosing regimen of recent drugs, the reporting of BMI and the possible exclusion of patients according to BMI, other adiposity measurements and/or diabetes (leading comorbidity of obesity). We further explored whether treatment efficacy was evaluated according to BMI. METHODS: A search of Pubmed and ClinicalTrials.gov was performed to identify phase I-IV trials investigating novel systemic breast cancer treatments. Dosing regimens and exclusion based on BMI, adiposity measurements or diabetes, documentation of BMI and subgroup analyses according to BMI were assessed. RESULTS: 495 trials evaluating 26 different drugs were included. Most of the drugs (21/26, 81%) were given in a fixed dose independent of patient weight. BMI was an exclusion criterion in 3 out of 495 trials. Patients with diabetes, the leading comorbidity of obesity, were excluded in 67/495 trials (13.5%). Distribution of patients according to BMI was mentioned in 8% of the manuscripts, subgroup analysis was performed in 2 trials. No other measures of adiposity/body composition were mentioned in any of the trials. Retrospective analyses on the impact of BMI were performed in 6 trials. CONCLUSIONS: Patient adiposity is hardly considered as most novel drug treatments are given in a fixed dose. BMI is generally not reported in recent trials and few secondary analyses are performed. Given the prevalence of patients with obesity and the impact obesity can have on pharmacokinetics and cancer biology, more attention should be given by investigators and study sponsors to reporting patient's BMI and evaluating its impact on treatment efficacy and toxicity.

Aging-accumulated methylmalonic acid serum levels at breast cancer diagnosis are not associated with distant metastases.

PURPOSE: Recent evidence suggests that age-accumulated methylmalonic acid (MMA) promotes breast cancer progression in mice. This study aims to investigate the association between baseline serum MMA concentrations in patients with breast cancer and the development of subsequent distant metastases. METHODS: We included 32 patients with early Luminal B-like breast cancer (LumB, median age 62.4y) and 52 patients with early triple-negative breast cancer (TNBC, median age 50.5y) who developed distant metastases within 5 years. They were matched to an equal number of early breast cancer patients (median age 62.2y for LumB and 50.5y for TNBC) who did not develop distant metastases with at least 5 years of follow-up. RESULTS: Baseline serum MMA levels at breast cancer diagnosis showed a positive correlation with age (P < 0.001) and a negative correlation with renal function and vitamin B12 (all P < 0.02), but no statistical association was found with BMI or tumor stage (P > 0.6). Between matched pairs, no significant difference was observed in MMA levels, after adjusting for kidney function and age (P = 0.19). Additionally, in a mouse model, a significant decline in MMA levels was observed in the tumor-bearing group compared to the group without tumors before and after tumor establishment or at identical times for the control group (P = 0.03). CONCLUSION: Baseline serum MMA levels in patients with breast cancer are not correlated with secondary distant metastasis. Evidence in the mouse model suggests that the presence of a tumor perturbates MMA levels.

Upper-Limb Movement Quality before and after Surgery in Women with Breast Cancer: An Exploratory Study.

(1) Background: This study aimed to describe upper-limb (UL) movement quality parameters in women after breast cancer surgery and to explore their clinical relevance in relation to post-surgical pain and disability. (2) Methods: UL movement quality was assessed in 30 women before and 3 weeks after surgery for breast cancer. Via accelerometer data captured from a sensor located at the distal end of the forearm on the operated side, various movement quality parameters (local dynamic stability, movement predictability, movement smoothness, movement symmetry, and movement variability) were investigated while women performed a cyclic, weighted reaching task. At both test moments, the Quick Disabilities of the Arm, Shoulder, and Hand (Quick DASH) questionnaire was filled out to assess UL disability and pain severity. (3) Results: No significant differences in movement quality parameters were found between the pre-surgical and post-surgical time points. No significant correlations between post-operative UL disability or pain severity and movement quality were found. (4) Conclusions: From this study sample, no apparent clinically relevant movement quality parameters could be derived for a cyclic, weighted reaching task. This suggests that the search for an easy-to-use, quantitative analysis tool for UL qualitative functioning to be used in research and clinical practice should continue.

Designing clinical trials based on modern imaging and metastasis-directed treatments in patients with oligometastatic breast cancer: a consensus recommendation from the EORTC Imaging and Breast Cancer Groups.

Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed.

The impact of mindfulness on cancer-related cognitive impairment in breast cancer survivors with cognitive complaints.

BACKGROUND: Interventions that target cancer-related cognitive impairment (CRCI) to improve the quality of life of cancer survivors are needed. In this study, the potential of a mindfulness-based intervention to reduce CRCI in breast cancer survivors, compared with physical training and a wait list control group, was investigated. METHODS: Breast cancer survivors with cognitive complaints (N = 117) were randomly allocated to a mindfulness (n = 43), physical training (n = 36), or wait list control condition (n = 38). Participants completed neuropsychological tests and questionnaires before the intervention, immediately after, and 3 months after intervention. The primary outcome measure was the change in cognitive complaints over time. Secondary outcomes were objective cognitive impairment and psychological well-being. All outcomes were compared between groups over time using linear mixed models, including participants with missing values. RESULTS: Of the 117 included participants, 96 completed the three assessments. Participants in the three groups reported decreased cognitive complaints after intervention, without group differences. There were no between-group differences in objective cognitive impairment after intervention compared with baseline. Compared with the wait list control group, participants reported increased mindfulness skills and reduced emotional distress after mindfulness and reduced emotional distress and fatigue after physical training. CONCLUSION: Contrary to the hypothesis, all groups reported an improvement in cognitive complaints over time. It is suggested that priming and acknowledgment of CRCI might alter the experience of cognitive impairment. Additionally, both mindfulness-based intervention and physical training can improve psychological well-being of breast cancer survivors with cognitive complaints.

Returning to Work After Breast Cancer Surgery: A Randomised Controlled Trial on the Effect of Pain Neuroscience Education.

PURPOSE: The aim of this study was to investigate the effect of pain neuroscience education compared to biomedical pain education after breast cancer surgery on (1) work status, (2) time until work resumption, and (3) change in return-to-work expectations up to 18 months post-surgery. METHODS: Participants were randomly assigned to either pain neuroscience education (intervention group) or biomedical pain education (control group) in addition to a standard physical therapy program after surgery for breast cancer. The first four months following surgery, one to two physiotherapy sessions and three educational sessions were scheduled. After, two educational sessions and two physiotherapy sessions were held at six and eight months postoperatively. All outcomes were assessed at four, six, eight, 12 and 18 months postoperatively. RESULTS: At 12 months, in the intervention group, 71% of the women returned to work compared to 53% in the control group (18% points difference, 95%CI:-0.1 to 35;p = 0.07). At 18 months, the differences decreased to 9% points, 95%CI:-26 to 7;p = 0.35). Neither time until work resumption (p = 0.46) nor change in estimation of own ability to return to work up to 18 months postoperatively (p = 0.21) significantly differed between both groups. CONCLUSION: No significant differences were found regarding return to work outcomes between women receiving pain neuroscience education versus biomedical pain education after breast cancer surgery. Further research is warranted to explore the potential role of pain neuroscience education in return-to-work interventions following breast cancer surgery.

Assessing Upper Limb Function in Breast Cancer Survivors Using Wearable Sensors and Machine Learning in a Free-Living Environment.

(1) Background: Being able to objectively assess upper limb (UL) dysfunction in breast cancer survivors (BCS) is an emerging issue. This study aims to determine the accuracy of a pre-trained lab-based machine learning model (MLM) to distinguish functional from non-functional arm movements in a home situation in BCS. (2) Methods: Participants performed four daily life activities while wearing two wrist accelerometers and being video recorded. To define UL functioning, video data were annotated and accelerometer data were analyzed using a counts threshold method and an MLM. Prediction accuracy, recall, sensitivity, f1-score, 'total minutes functional activity' and 'percentage functionally active' were considered. (3) Results: Despite a good MLM accuracy (0.77-0.90), recall, and specificity, the f1-score was poor. An overestimation of the 'total minutes functional activity' and 'percentage functionally active' was found by the MLM. Between the video-annotated data and the functional activity determined by the MLM, the mean differences were 0.14% and 0.10% for the left and right side, respectively. For the video-annotated data versus the counts threshold method, the mean differences were 0.27% and 0.24%, respectively. (4) Conclusions: An MLM is a better alternative than the counts threshold method for distinguishing functional from non-functional arm movements. However, the abovementioned wrist accelerometer-based assessment methods overestimate UL functional activity.

Biopsychosocial risk factors for pain and pain-related disability 1 year after surgery for breast cancer.

PURPOSE: Knowledge regarding risk factors for pain in the long term after surgery for breast cancer may be of great value in preventing this prevalent and debilitating side effect. Despite the biopsychosocial nature of pain, the predictive value of both pre- and postoperative biopsychosocial functioning for long-term pain intensity and pain-related disability has not yet been studied. METHODS: One hundred sixty-six women planned for unilateral breast cancer surgery were included in this prospective cohort study. Pre- and postoperative outcomes related to pain, psychosocial, and somatosensory functioning (questionnaires and quantitative sensory testing) were evaluated as risk factors for pain intensity (visual analog scale) and pain-related disability (pain disability index) 1 year after surgery for breast cancer. Both bivariable and stepwise linear regression analyses were performed. RESULTS: The most consistent biopsychosocial risk factors were symptoms related to altered central somatosensory functioning (central sensitization inventory), psychological symptoms, and social support (psychological symptoms and support subscale of McGill Quality of Life Questionnaire). Results also showed that a pre- and postoperative disturbed functioning of the somatosensory nervous system in the surgical area could provide additional information regarding pain intensity or pain-related disability in the long term after surgery for breast cancer. CONCLUSION: This study revealed several biopsychosocial characteristics that might be used to identify women more vulnerable to have pain and pain-related disability in the long term after surgery for breast cancer, allowing for more effective pain management and prevention.

Absolute and Relative Reliability of a Comprehensive Quantitative Sensory Testing Protocol in Women Treated for Breast Cancer.

OBJECTIVE: Quantitative sensory testing (QST) consists of noninvasive psychophysical assessment techniques to evaluate the functioning of the somatosensory nervous system. Despite the importance of reliability for the correct use of QST results in research and clinical practice, the relative and absolute intra- and inter-rater reliability of a comprehensive QST protocol to evaluate the functioning of both the peripheral and central somatosensory nervous system in a breast cancer population has not yet been investigated. SETTING: University Hospitals, Leuven, Belgium. SUBJECTS: Thirty women at least 6 months after unilateral breast cancer surgery. METHODS: The protocol included nine static and dynamic QST methods (mechanical pain-detection thresholds, pressure pain thresholds, thermal pain-detection thresholds for heat and cold, temporal summation, and conditioned pain modulation [CPM]) performed in the surgical area and in more distant regions. Absolute and relative intra-rater reliability (60-minute interval) and inter-rater reliabilty (1-week interval) were evaluated with intraclass correlation coefficients, standard error of measurement, and Bland-Altman plots. RESULTS: Moderate to excellent relative intra-rater reliability and inter-rater reliability were found for the evaluation of mechanical thresholds, pressure pain thresholds, and temporal summation. The reliability of the CPM paradigm was considered weak. Systematic bias between raters was noticed for the detection of mechanical and cold stimuli at the non-affected trunk and for CPM. CONCLUSIONS: Except for the evaluation of CPM, the QST protocol was found suitable for identifying differences between subjects (relative reliability) and for individual follow-up after breast cancer surgery (limited systematic bias) during a 1-week time frame. Additional research is required to determine the measurement properties that influence CPM test stability to establish a more reliable CPM test paradigm.

Concordance between results of inexpensive statistical models and multigene signatures in patients with ER+/HER2- early breast cancer.

Multigene signatures (MGS) are used to guide adjuvant chemotherapy (aCT) decisions in patients diagnosed with estrogen receptor (ER)-positive HER2-negative early breast cancer. We used results from three MGS (Oncotype DX® (ODX), MammaPrint® (MP) or Prosigna®) and assessed the concordance between high or low risk of recurrence and the predicted risk of recurrence based on statistical models. In addition, we looked at the impact of MGS results on final aCT administration during the multidisciplinary meeting (MDM). We retrospectively included 129 patients with ER-positive HER2-negative early breast cancer for which MGS testing was performed after MDM at University Hospitals Leuven between May 2013 and April 2019 in case there was doubt about aCT recommendation. Tumor tissue was analyzed either by ODX (N = 44), MP (N = 28), or Prosigna® (N = 57). Eight statistical models were computed: Magee equations (ME), Memorial Sloan Kettering simplified risk score (MSK-SRS), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL), Mymammaprint.com (MyMP), PREDICT, and SiNK. Concordance, negative percent agreement, and positive percent agreement were calculated. Of 129 cases, 53% were MGS low and 47% MGS high risk. Concordances of 100.0% were observed between risk results obtained by ODX and ME. For MP, BCRSE demonstrated the best concordance, and for Prosigna® the average of ME. Concordances of <50.0% were observed between risk results obtained by ODX and nAOL, ODX and MyMP, ODX and SiNK, MP and MSK-SRS, MP and nAOL, MP and MyMP, MP and SiNK, and Prosigna® and ODXC. Integration of MGS results during MDM resulted in change of aCT recommendation in 47% of patients and a 15% relative and 9% absolute reduction. In conclusion, statistical models, especially ME and BCRSE, can be useful in selecting ER-positive HER2-negative early breast cancer patients who may need MGS testing resulting in enhanced cost-effectiveness and reduced delay in therapeutic decision-making.

Effects of a mindfulness-based intervention on cancer-related cognitive impairment: Results of a randomized controlled functional magnetic resonance imaging pilot study.

BACKGROUND: Many breast cancer survivors suffer from cognitive complaints after cancer treatment, affecting their quality of life. The objective of this pilot study was to investigate the effect of a blended-care mindfulness-based intervention (MBI) on chemotherapy-related cognitive impairment and functional brain changes. Furthermore, correlations between changes in cognitive functioning and self-reported behavioral factors were investigated. METHODS: Breast cancer survivors (n = 33) who reported cognitive impairment were randomly allocated to a mindfulness condition (n = 18) or a waitlist control condition (n = 15). Patients completed questionnaires on cognitive impairment, emotional distress, and fatigue; neuropsychological tests; and resting-state functional magnetic resonance imaging before the start of MBI (time 1 [T1]), immediately after the completion of an 8-week MBI program (T2), and 3 months postintervention (T3). Resting-state functional connectivity was estimated in the default mode network, the dorsal and salience attention networks, and the frontoparietal network. Mixed model repeated-measures analysis was performed to test the intervention effect. RESULTS: Patients in the mindfulness condition exhibited significantly higher connectivity between the dorsal and salience attention networks after the mindfulness intervention compared with those in the control condition. MBI participants also had reduced subjective cognitive impairment, emotional distress, and fatigue. No intervention effect was observed on neurocognitive tests. CONCLUSIONS: MBI may induce functional brain changes in networks related to attention and may have a positive effect on subjective measures of cognitive impairment in breast cancer survivors. Therefore, MBI could be a suitable intervention to improve quality of life in this population and deserves further study in this context.

Behavior of metastatic breast cancer according to subtype.

PURPOSE: To explore the impact of breast cancer subtype on metastatic behavior and long-term outcome defined as breast cancer specific survival (BCSS). METHODS: Retrospective single centre cross-sectional study of 5972 patients with newly diagnosed, unilateral first diagnosis of breast cancer, diagnosed 2000-2010. Patients had either early breast cancer (EBC) treated primarily by surgery (SURG n = 5072), neoadjuvant systemic therapy (NEO n = 592), or upfront metastatic disease (META n = 308). Surrogate breast cancer subtypes were defined according to classical pathological criteria. Analysis was performed using Kaplan-Meier method and logistic/Cox regression. RESULTS: After median follow-up time of 103.6 months (IQR 73.4-139.2 months), 817 patients with EBC at diagnosis (14.4%) developed distant metastases of which 621 (12.2%) SURG and 196 (33.1%) NEO. Metastasis rate after EBC was: LuminalA 8.1%, LuminalB1(HER2-) 20.4%, LuminalB2(HER2+) without (neo)adjuvant trastuzumab 21.7%, LuminalB2(HER2+) with trastuzumab 9.0%, HER2Positive(ER-) without trastuzumab 30.0%, HER2Positive(ER-) with trastuzumab 19.9% and TripleNegative 25.3%. There were major differences in site of first metastases according to subtype. For single site first metastases, median BCSS assessed from time of metastases was worst for brain localization (13.9 months) and best for bone (48.4 months). Multiple sites of first metastases had worse BCSS from date of metastases than single site first metastases (median BCSS for 1 site 40.0, 2 sites 27.1, ≥ 3 sites 20.5 months). Median BCSS from date of metastases is longer in upfront metastases compared to secondary metastases after EBC (43.4 vs. 27.9 months). CONCLUSIONS: Tumor subtype influences the metastatic behavior and survival after development of distant metastases.

Assessment of stromal tumor infiltrating lymphocytes and immunohistochemical features in invasive micropapillary breast carcinoma with long-term outcomes.

PURPOSE: We studied the long-term outcomes of invasive micropapillary carcinoma (IMPCs) of the breast in relation to stromal tumor infiltrating lymphocytes (sTILs), prognostic biomarkers and clinicopathological features. METHODS: Stage I-III IMPCs treated with upfront surgery at our institution (January 2000 and December 2016) were included. Central pathology review was performed and sTILs (including zonal distribution and hot spot analysis) and tumor-associated plasma cells (TAPC) were evaluated. Expression of P53, BCL2, FOXP3, and WT1, which are variably linked to breast cancer prognosis, was measured by immunohistochemistry using tissue microarrays. Time-to-event endpoints were distant recurrence free interval (DRFI) and breast cancer-specific survival (BCSS). RESULTS: We included 111 patients of whom 59% were pure IMPCs. Standard clinicopathological features were comparable between pure and non-pure IMPCs. Overall, the mean sTILs level was 20% with higher proportion of sTILs present at the invasive front. There were no significant differences between pure- and non-pure IMPCs in sTILs levels, nor in the spatial distribution of the hot spot regions or in the distribution of TAPC. Higher sTILs correlated with worse DRFI (HR = 1.55; p = 0.0172) and BCSS (HR = 2.10; p < 0.001). CONCLUSIONS: Clinicopathological features, geographical distribution of sTILs and TAPC are similar between pure and non-pure IMPCs. Despite a high proportion of grade 3 tumors and lymph node involvement, we observed a low rate of distant recurrences and breast cancer-related death in this cohort of stage I-III IMPCs treated with primary surgery. Caution in interpretation of the observed prognostic correlations is required given the very low number of events, warranting validation in other cohorts.

The added value of geriatric assessment in evaluating a patient's Health-Related Quality-of-Life: A study in ≥70-year-old early-stage invasive breast cancer patients.

OBJECTIVE: The objective of this study was to assess the relationship between geriatric assessment (GA) and health-related Quality-of-Life (HRQOL) in older patients with breast cancer. METHODS: Patients were assigned either to adjuvant chemotherapy (CTG) or to a control group (CG). Spearman rank coefficients (ρ) calculated correlations between HRQOL and GA at baseline, 3 months and 1 year. Multivariate regressions modelled the prognostic value of GA in evaluating of a patient's HRQOL and the accuracy of baseline GA in predicting HRQOL decline (change of ≥10 points). RESULTS: The analysis included 57 patients in the CTG and 52 in the CG. Strong correlations (ρ ≥ 0.5) were reported between the EORTC QLQ-C30 Physical Functioning Scale and Activities of Daily Living (ADL), Instrumental ADL (iADL) and Leuven Oncogeriatric Frailty Score Scale (LOFS). Multivariate models demonstrated that poor iADL, ADL and LOFS (CG) and ADL and iADL (CTG) contributed to a statistically (all p < .05) worse HRQOL. The relative gain in predicting 3-month and 1-year HRQOL decline was 24.1% and 4.7% (CG) and 6.1% and 18.3% (CTG). CONCLUSION: Our results show that the functional measures in the GA are strongly correlated with patient self-reported functioning. Poor baseline GA has a modest probability of predicting HRQOL deterioration.

Prognostic Value of the Progesterone Receptor by Subtype in Patients with Estrogen Receptor-Positive, HER-2 Negative Breast Cancer.

BACKGROUND: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER-2) negative breast cancers, the progesterone receptor (PR) is an independent prognostic marker. Little is known about the prognostic value of PR by tumor grade. We assessed this in two independent datasets. PATIENTS AND METHODS: Women with primary operable, invasive ER+ HER-2 negative breast cancer diagnosed between 2000 and 2012, treated at University Hospitals Leuven, were included. We assessed the association of PR status and subtype (grade 1-2 vs. grade 3) with distant recurrence-free interval (DRFI) and breast cancer-specific survival. The interaction between PR status and subtype was investigated, and associations of PR status by subtype were calculated. The BIG 1-98 data set was used for validation. RESULTS: In total, 4,228 patients from Leuven and 5,419 from BIG 1-98 were analyzed. In the Leuven cohort, the adjusted hazard ratio (HR) of PR-positive versus PR-negative tumors for DRFI was 0.66 (95% confidence interval [CI], 0.50-0.89). For the interaction with subtype (p = .34), the HR of PR status was 0.79 (95% CI, 0.61-1.01) in luminal A-like and 0.59 (95% CI, 0.46-0.76) in luminal B-like tumors. In luminal A-like tumors, observed 5-year cumulative incidences of distant recurrence were 4.1% for PR-negative and 2.8% for PR-positive tumors, and in luminal B-like 18.7% and 9.2%, respectively. In the BIG 1-98 cohort, similar results were observed; for the interaction with subtype (p = .12), the adjusted HR of PR status for DRFI was 0.88 (95% CI, 0.57-1.35) in luminal A-like and 0.58 (95% CI, 0.43-0.77) in luminal B-like tumors. Observed 5-year cumulative incidences were similar. CONCLUSION: PR positivity may be more protective against metastatic relapse in luminal B-like versus luminal A-like breast cancer, but no strong conclusions can be made. In absolute risk, results suggest an absent PR is clinically more important in high compared with low proliferative ER+ HER-2 negative tumors. IMPLICATIONS FOR PRACTICE: An absent progesterone receptor (PR) predicts a worse outcome in women treated for an estrogen receptor-positive, human epidermal growth factor receptor 2 negative breast cancer. As low proliferative tumors lacking PR are now also classified high risk, the prognostic value of PR across risk groups was studied. Despite a negative test for interaction of the prognostic value of PR by tumor grade, the magnitude of an absent PR on breast cancer relapse is much larger in high than in low proliferative breast cancers.

Age-dependent brain volume and neuropsychological changes after chemotherapy in breast cancer patients.

This study investigated volumetric brain changes and cognitive performance in premenopausal and postmenopausal patients treated for early-stage breast cancer. Participants underwent elaborate neurocognitive assessments (neuropsychological testing, cognitive failure questionnaire, and high-resolution T1-weighted structural MRI) before and after chemotherapy. Volumetric brain changes were estimated, using longitudinal deformation-based morphometry, and correlated with cognitive changes. In total, 180 women participated in this study, of whom 72 patients with breast cancer had received adjuvant chemotherapy (C+), 49 patients did not receive chemotherapy (C-), and 59 healthy controls (HC). The population was categorized into two age groups: A young group who were premenopausal and younger than 52 years at baseline (n = 55C+/32C-/41HC), and an older group who were postmenopausal and older than 60 years (n = 17C+/17C-/18HC). Cognitive impairment occurred after chemotherapy in both young and older patients, although older patients showed more decline in processing speed (Trail making test b). White matter volume expansion was observed after chemotherapy, only significantly present in the younger subgroup of patients. In patients not treated with chemotherapy, diffuse gray and white matter volume reduction was observed. Less white matter expansion concurred with more cognitive decline (r > .349, p < .05). In conclusion, we found age-dependent cognitive decline and white matter volume changes in patients with breast cancer after chemotherapy, which could possibly be linked to neuroinflammatory processes. White matter expansion after chemotherapy, more pronounced in premenopausal patients, correlated with less cognitive decline. This suggests such expansion to be age-dependent, possibly caused by a protective response in the younger brain to chemotherapy-induced neurotoxicity.

Tumor characteristics and outcome by androgen receptor expression in triple-negative breast cancer patients treated with neo-adjuvant chemotherapy.

PURPOSE: To assess clinical pathological characteristics and outcome of triple-negative breast cancers (TNBC) by androgen receptor (AR) protein expression. METHODS: We retrospectively evaluated AR by immunohistochemistry on core-needle biopsy, (CNB) and residual disease (RD) in a consecutive institutional series of TNBC patients treated with neo-adjuvant chemotherapy (NACT) between 2000 and 2017. We investigated univariate associations between AR-expression on CNB (using different cut-offs), clinical pathological variables, and pathologic complete response (pCR). Next, we used multiple correspondence analysis (MCA) to investigate the relationships between AR on CNB and standard clinical and pathological variables, including stromal tumor infiltrating lymphocytes (sTILs). Finally, we investigated the prognostic value of AR-expression on CNB and RD using the Fine and Gray model. RESULTS: We included 71 patients; median follow-up was 6.7 years. Considering the ≥ 1% cut-off, AR was present in 32% on the CNB and 14% on RD. AR-low (1-34% positive tumor cells) patients were associated with younger (premenopausal) age and AR-high (≥ 34% positive tumor cells) with older (postmenopausal) age. AR on CNB did not correlate with other features nor was it predictive for pCR or prognostic for metastatic outcome, regardless of the used cut-off. The MCA suggested that body mass index (BMI) affects the predictive role of AR-low and -high for pCR differently. AR-loss on RD was prognostic for a better 5-year distant disease-free survival (DDFS) as compared to RD with retained AR-expression (61.6% (95% CI 44.26-79.14) and 25.0% (95% CI 3.94-87.21), respectively; p = 0.01). CONCLUSION: Low and high AR-expression on CNB of TNBC were correlated with age and menopausal status but qualitative AR was not predictive for pCR. AR-loss on RD was prognostic for DDFS in TNBC patients treated with NACT.

Oncological safety of autologous breast reconstruction after mastectomy for invasive breast cancer.

BACKGROUND: The number of patients requesting autologous breast reconstruction (ABR) after mastectomy for breast cancer has increased over the past decades. However, concern has been expressed about the oncological safety of ABR. The aim of our study was to assess the effect of ABR on distant relapse. METHODS: In this retrospective cohort study, data was analysed from patients who underwent mastectomy for invasive breast cancer in University Hospitals Leuven between 2000 and 2011. In total, 2326 consecutive patients were included, 485 who underwent mastectomy with ABR and 1841 who underwent mastectomy alone. The risk of relapse in both groups was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. ABR was considered as a time-dependent variable. Additionally, the evolution of the risk over follow-up time was calculated. RESULTS: With a median follow-up of 68 months, 8% of patients in the reconstruction group developed distant metastases compared to 15% in the mastectomy alone group (univariate HR 0.70, 95% CI 0.50-0.97, p = 0.0323). However, after adjustment for potential confounding factors in a Cox multivariable analysis, the risk of distant relapse was no longer significantly different between groups (multivariate HR 0.82, 95% CI 0.55-1.22, p = 0.3301). Moreover, the risk of metastasis after reconstruction was not time-dependent. CONCLUSIONS: These findings suggest that there is no effect of ABR on distant relapse rate and thus that ABR is an oncological safe procedure. The rate of local recurrence was too low to make any significant conclusions.

Age-related microRNAs in older breast cancer patients: biomarker potential and evolution during adjuvant chemotherapy.

BACKGROUND: MicroRNAs (miRNAs) are important regulators of cellular function and have been associated with both aging and cancer, but the impact of chemotherapy on age-related miRNAs has barely been studied. Our aim was to examine whether chemotherapy accelerates the aging process in elderly breast cancer patients using miRNA expression profiling. METHODS: We monitored age-related miRNAs in blood of women, aged 70 or older, receiving adjuvant chemotherapy (docetaxel and cyclophosphamide, TC) for invasive breast cancer (chemo group, CTG, n = 46). A control group of older breast cancer patients without chemotherapy was included for comparison (control group, CG, n = 43). All patients underwent geriatric assessment at inclusion (T0), after 3 months (T1) and 1 year (T2). Moreover, we analysed the serum expression of nine age-related miRNAs (miR-20a, miR-30b, miR-34a, miR-106b, miR-191, miR-301a, miR-320b, miR-374a, miR-378a) at each timepoint. RESULTS: Except for miR-106b, which behaved slightly different in CTG compared to CG, all miRNAs showed moderate fluctuations during the study course with no significant differences between groups. Several age-related miRNAs correlated with clinical frailty (miR-106b, miR-191, miR-301a, miR-320b, miR-374a), as well as with other biomarkers of aging, particularly Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1) (miR-106b, miR-301a, miR-374a-5p, miR-378a-3p). Moreover, based on their 'aging miRNA' profiles, patients clustered into two distinct groups exhibiting significantly different results for several biological/clinical aging parameters. CONCLUSIONS: These results further corroborate our earlier report, stating that adjuvant TC chemotherapy does not significantly boost aging progression in elderly breast cancer patients. Our findings also endorsed specific age-related miRNAs as promising aging/frailty biomarkers in oncogeriatric populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00849758 . Registered on 20 February 2009. This clinical trial was registered prospectively.

Effectiveness of Botulinum Toxin A for Persistent Upper Limb Pain After Breast Cancer Treatment: A Double-Blinded Randomized Controlled Trial.

OBJECTIVE: To investigate the effect of a single botulinum toxin A (BTX-A) infiltration in the pectoralis major muscle in addition to a standard physical therapy program for treatment of persistent upper limb pain in breast cancer survivors. DESIGN: Double-blinded (patient and assessor) randomized controlled trial. SETTING: A university hospital. PARTICIPANTS: Breast cancer patients (N=50) with pain. INTERVENTION: The intervention group received a single BTX-A infiltration. The control group received a placebo (saline) infiltration. Within 1 week after the infiltration, all patients attended an individual physical therapy program (12 sessions) during the first 3 months and a home exercise program up to 6 months after infiltration. MAIN OUTCOME MEASURES: The primary outcome was change in pain intensity at the upper limb (visual analog scale, 0-100) after 3 months. Secondary outcomes were prevalence rate of pain, pressure hypersensitivity, pain quality, shoulder function, and quality of life. Measures were taken before the intervention and at 1, 3, and 6 months' follow-up. RESULTS: No significant difference in change in pain intensity after 3 months was found (mean difference in change, 3/100; 95% confidence interval [CI], -13 to 19). From baseline up to 6 months, a significantly different change in upper limb pain intensity was found between groups in favor of the intervention group (mean difference in change, 16/100; 95% CI, 1-31). CONCLUSIONS: A single BTX-A infiltration in combination with an individual physical therapy program significantly decreased pain intensity at the upper limb in breast cancer survivors up to 6 months. However, the effect size was not clinically relevant, and no other beneficial effects were found.