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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, β = 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: β = 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 [ABSTRACT FROM AUTHOR]

Background: Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement. Methods: Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n = 424), and a Dutch prospective clinical cohort called MST (n = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan–Meier method, log-rank tests and Cox's proportional hazard models were used for survival analysis. Results: In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15–0.75). Conclusions: We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment. [ABSTRACT FROM AUTHOR]

Purpose: Describes the relevance of –various classification methods for ipsilateral breast tumour recurrence (IBTR) as either true recurrence (TR) or new primary (NP) on both disease-specific survival (DSS) and distant metastasis-free survival (DMFS). Method: Two hundred and thirty-four of 4359 women undergoing breast-conserving therapy experienced IBTR. We compared the impact of four known classification methods and two newly created classification methods. Results: For three of the methods, a better DSS was observed for NP compared to TR with the hazard ratio (HR) ranging from 0.5 to 0.6. The new Twente method classification, comprising all classification criteria of three known methods, and the new Morphology method, using only morphological criteria, had the best HR and confidence interval with a HR 0.5 (95% CI 0.2–1.0) and a HR 0.5 (95% CI 0.3–1.1), respectively. For DMFS, the HR for NP compared to TR ranged from 0.6 to 0.9 for all six methods. The new Morphology method and the Twente method noted the best HR and confidence intervals with a HR 0.6 (95% CI 0.3–1.1) and a HR 0.6 (95% CI 0.4–1.2), respectively. Conclusion: IBTR classified as TR or NP has a prognostic value for both DSS and DMFS, but depends on the classification method used. Developing and validating a generally accepted form of classification are imperative for using TR and NP in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of the timing of radiation therapy after breast-conserving surgery in relation to distant metastasis-free survival and disease-specific survival.Methods: The analysis was performed in relation to 4189 women all undergoing breast-conserving therapy (BCT). Three groups were defined with respect to lymph node status and the use of adjuvant systemic therapy (AST). Patients were categorized into time intervals: < 37 days, 37-53 days, 54-112 days and > 112 days.Results: For women without lymph node metastases and with favourable characteristics aged > 55 years, an improved treatment efficacy was noted when starting radiotherapy with a time interval of < 37 days. The same was observed for women with lymph nodes metastases receiving AST aged ≤ 50 years. Finally, for women aged > 50 years with negative lymph node status but with unfavourable characteristics and receiving AST, an improved treatment efficacy was noted when starting radiotherapy after a time interval of ≥ 37 days.Conclusion: The results of our study further support the hypothesis that the timing of radiotherapy may have an impact on treatment efficacy and that further studies (preferably randomized trials) are indicated. [ABSTRACT FROM AUTHOR]

Background: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort.Methods: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided.Results: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for "other" vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, "other," and MLH1-hypermethylated MMRd-EC groups, respectively.Conclusions: The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to evaluate the prognostic value of the Mitotic Activity Index (MAI) in combination with the human epidermal growth factor receptor (Her2) for distant metastases-free survival (DMFS) and disease-specific survival (DSS) in breast cancer and compare it with the immunohistochemically (IHC) profile types. Methods: Analyses were based on 2.923 breast-conserving breast cancer specimens with known MAI, Her2 status, and hormone receptor status, resulting in 2.678 Her2MAI combinations, MAI ≤ 12/Her2negative, MAI > 12/Her2negative, MAI > 12/Her2positive, and MAI ≤ 12/Her2positive, and 2.560 IHC profile types, luminal A, luminal B, triple negative, and non-luminal Her2positive. Results: For DMFS, the MAI > 12/Her2negative combination showed a significantly worse outcome in multivariate analyses compared to the MAI ≤ 12/Her2negative combination. None of the IHC profile types showed significantly different outcomes for DMFS and DSS as compared to luminal A. We performed a separate analysis on age and lymph node status. The significance of MAI > 12/Her2negative seems to be limited to women ≤ 55 years for both DMFS and DSS. However, with respect to DSS, this seems to be limited to node negative cases. The IHC profile types for DSS, luminal B showed a significantly worse outcome for women > 55 years compared to that for luminal A, although it showed rather wide confidence interval. Conclusion: The MAI > 12/Her2negative combination seems to be a strong prognosticator for DMFS and DSS, particularly for women ≤ 55 years. However, none of the IHC profile types seems to be a prognosticator in breast cancer. [ABSTRACT FROM AUTHOR]

The utilization rate of RT increased from 64.4% in 2011 to 70.3% in 2015. After BCS and mastectomy, 97.3% and 26.1% of the patients received RT, respectively. For patients undergoing BCS and mastectomy, lower age and ER + tumours were associated with higher RT utilisation rates. After mastectomy, also larger tumour sizes, lymph node involvement, grade‐2 and 3 tumours and diagnosis in more recent years were associated with higher RT use. [ABSTRACT FROM AUTHOR]

Introduction After treatment with chemotherapy, many patients with breast cancer experience cognitive problems. While limited interventions are available to improve cognitive functioning, physical exercise showed positive effects in healthy older adults and people with mild cognitive impairment. The Physical Activity and Memory study aims to investigate the effect of physical exercise on cognitive functioning and brain measures in chemotherapy-exposed patients with breast cancer with cognitive problems. Methods and analytics One hundred and eighty patients with breast cancer with cognitive problems 2-4 years after diagnosis are randomised (1:1) into an exercise intervention or a control group. The 6-month exercise intervention consists of twice a week 1-hour aerobic and strength exercises supervised by a physiotherapist and twice a week 1-hour Nordic or power walking. The control group is asked to maintain their habitual activity pattern during 6 months. The primary outcome (verbal learning) is measured at baseline and 6 months. Further measurements include online neuropsychological tests, self-reported cognitive complaints, a 3-tesla brain MRI, patient-reported outcomes (quality of life, fatigue, depression, anxiety, work performance), blood sampling and physical fitness. The MRI scans and blood sampling will be used to gain insight into underlying mechanisms. At 18 months online neuropsychological tests, self-reported cognitive complaints and patient-reported outcomes will be repeated. Ethics and dissemination Study results may impact usual care if physical exercise improves cognitive functioning for breast cancer survivors. [ABSTRACT FROM AUTHOR]

Background: The primary aim of the study was to investigate prognosis and long-term survival in young breast cancer patients with a BRCA1 or BRCA2 germline mutation compared with noncarriers. The secondary aim was to investigate whether differences in survival originate from associations with tumor characteristics, second cancers, and/or treatment response.Methods: We established a cohort of invasive breast cancer patients diagnosed younger than age 50 years in 10 Dutch hospitals between 1970 and 2003. BRCA1/2 testing of most prevalent mutations was mainly done using DNA isolate from formalin-fixed paraffin-embedded nontumor tissue. Survival estimates were derived using Cox regression and competing risk models.Results: In 6478 breast cancer patients, we identified 3.2% BRCA1 and 1.2% BRCA2 mutation carriers. BRCA1 mutation carriers had a worse overall survival independent of clinico-pathological/treatment characteristics, compared with noncarriers (adjusted hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 0.97 to 1.47), though only statistically significant in the first five years of follow-up (adjusted HR = 1.40, 95% CI = 1.07 to 1.84). A large part of the worse survival was explained by incidence of ovarian cancers. Breast cancer-specific, disease-free, and metastasis-free survival results were less pronounced and mostly statistically nonsignificant but in the same direction with those of overall survival. Overall survival was worse, although not statistically significantly, within the ER-negative or ER-positive, grade 3, and small tumor subgroups. The worse survival was most pronounced in non-chemotherapy-treated patients (adjusted HR = 1.54, 95% CI = 1.08 to 2.19). Power for BRCA2 mutation carriers was limited; only after five years' follow-up overall survival was worse (adjusted HR = 1.47, 95% CI = 1.00 to 2.17).Conclusions: BRCA1/2 mutation carriers diagnosed with breast cancer before age 50 years are prone to a worse survival, which is partly explained by differences in tumor characteristics, treatment response, and second ovarian cancers. [ABSTRACT FROM AUTHOR]

Background:The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease-free survival (DFS) in a Dutch population-based cohort.Methods:All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes.Results:Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38-0.94)) and 42-55 days (HR 0.64 (95% CI: 0.45-0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42-55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days.Conclusions:Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned. [ABSTRACT FROM AUTHOR]

Background.The aim of this study is to analyze the impact of first degree relative (FDR) of young breast cancer patients. Methods.Data were used from our prospective population-based cohort study which started in 1983. The family history (FH) was registered with regard to FDR: the presence or absence of invasive breast cancer in none vs. one or more FDRs at any age. Results.A total of 1109 women, ≤50 years with 1128 breast conserving treatments was seen. The incidence of FDR was 17.0% for one FDR and 3.2% ≥2 FDR. The three groups, none, 1 or ≥2 FDR, were comparable. The local failure rate is comparable for all three groups. Women with a positive FH and metachronous bilateral breast cancer (MBBC) showed a lower local failure (HR 0.2; 95% CI 0.05–0.8). A positive FH was an independent predictor for a better disease-specific survival (HR 0.6; 95% CI 0.4–0.9). Conclusion.A positive FH, based on FDR implies a better prognosis in relation to survival for young women treated with BCT. In contrast to no FH for FDR, MBBC in women with a positive FH was not associated with an increased risk of local recurrence. [ABSTRACT FROM PUBLISHER]

Objective. The aim of this study is to look at possible differences in outcome between serosa and adnexal involvement stage IIIA endometrial carcinoma. Methods. 67 patients with stage IIIA endometrial carcinoma were included, 46 with adnexal involvement and 21 with serosa. A central histopathological review was performed. Results. The 7-year locoregional failure rate was (LRFR) 2.2% for adnexal involvement and 16.0% for involvement of the serosa (P = .0522). The 7-year distant metastasis-free survival was 72.7% for adnexal involvement and 58.7% for serosa (P = .3994). The 7-year disease-specific survival (DSS) was 71.8% for patients with adnexal involvement and 75.4% for patients with serosa. Conclusion. Endometrial carcinoma stage IIIA with involvement of the adnexa or serosa showed to have a comparable disease-specific survival. Locoregional control was worse for serosa involvement compared to adnexa. [ABSTRACT FROM AUTHOR]

A study of the possible difference in outcome for positive margins for invasive carcinoma (IC) versus ductal carcinoma in situ (DCIS), and with regard to different age categories in a large prospective cohort of patients with invasive breast cancer. A total of 2 291 BCT were analyzed. Margins were positive for IC in 8.7% and for DCIS in 4.6%. The median follow-up was 83 months. The 10-year local recurrence-free survival for negative margins vs. positive margins for IC vs. positive for DCIS for women ≤40 years were 84.4% vs. 34.6% (HR 4.5) vs. 67.5%, and for women >40 years 94.7% vs. 92.6% vs. 82.6% (HR4.2). The 10-year distant disease-free survival for negative margins vs. positive margins for IC vs. positive for DCIS women ≤40 years were 72.0% vs. 39.7% (HR 3.4) vs. 77.8%. The disease-specific survival showed a significant relation to positive margins for IC in young women. The effect of positive margin for IC seems to be limited to young women only, and is not only restricted to local control, but also to distant metastasis and survival. On the other hand a positive margin for DCIS is a risk factor for local control in women >40 years. [ABSTRACT FROM AUTHOR]

Background: The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease-free survival (DFS) in a Dutch population-based cohort.Methods: All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes.Results: Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38-0.94)) and 42-55 days (HR 0.64 (95% CI: 0.45-0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42-55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days.Conclusions: Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned. [ABSTRACT FROM AUTHOR]

Background: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis.Methods: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided.Results: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06).Conclusion: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC. [ABSTRACT FROM AUTHOR]

Background: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. Methods: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. Results: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). Conclusion: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC. [ABSTRACT FROM PUBLISHER]