Characterizing Frontal Lobe Seizure Semiology in Children.

OBJECTIVE: The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in focal epilepsy. METHODS: Fifty patients were identified retrospectively, who achieved seizure freedom after frontal lobe resective surgery at Great Ormond Street Hospital. Video-electroencephalography recordings of preoperative ictal seizure semiology were analyzed, stratifying the data based on resection region (mesial or lateral frontal lobe) and age at surgery (≤4 vs >4). RESULTS: Pediatric frontal lobe epilepsy is characterized by frequent, short, complex seizures, similar to adult cohorts. Children with mesial onset had higher occurrence of head deviation (either direction: 55.6% vs 17.4%; p = 0.02) and contralateral head deviation (22.2% vs 0.0%; p = 0.03), ictal body-turning (55.6% vs 13.0%; p = 0.006; ipsilateral: 55.6% vs 4.3%; p = 0.0003), and complex motor signs (88.9% vs 56.5%; p = 0.037). Both age groups (≤4 and >4 years) showed hyperkinetic features (21.1% vs 32.1%), contrary to previous reports. The very young group showed more myoclonic (36.8% vs 3.6%; p = 0.005) and hypomotor features (31.6% vs 0.0%; p = 0.003), and fewer behavioral features (36.8% vs 71.4%; p = 0.03) and reduced responsiveness (31.6% vs 78.6%; p = 0.002). INTERPRETATION: This study presents the most extensive semiological analysis of children with confirmed frontal lobe epilepsy. It identifies semiological features that aid in differentiating between mesial and lateral onset. Despite age-dependent differences, typical frontal lobe features, including hyperkinetic seizures, are observed even in very young children. A better understanding of pediatric seizure semiology may enhance the accuracy of onset identification, and enable earlier presurgical evaluation, improving postsurgical outcomes. ANN NEUROL 2024;95:1138-1148.

70-Gene signature-guided adjuvant systemic treatment adjustments in early-stage ER+ breast cancer patients: 7-year follow-up of a prospective multicenter cohort study.

BACKGROUND: A previous prospective multicenter study revealed the change of the oncologists' chemotherapy advice due to the 70-Gene signature (GS) test result in half of the estrogen receptor-positive (ER+) invasive early-stage breast cancer patients with disputable chemotherapy indication. This resulted in less patients receiving chemotherapy. This study aims to complement these results by the 7-year oncological outcomes according to the 70-GS test result and the oncologists' pre-test advice. METHODS: Patients operated for early-stage ER+ breast cancer with disputable chemotherapy indication, had been prospectively included between 2013 and 2015. Oncologists were asked whether they intended to administer adjuvant chemotherapy before deployment of the 70-GS test. Information on adjuvant systemic treatment and oncological outcome was obtained through active follow-up by data managers of the Netherlands Cancer Registry. The primary endpoint of this study was distant metastasis-free survival (DMFS) according to the genomic risk. Exploratory analyses were done to evaluate DMFS in relation to the oncologists' pre-test advice. RESULTS: After a median follow-up of 7 years, distant metastases were diagnosed in 23 of the 606 patients (3.8%) and 36 (5.9%) patients had died. The DMFS rate for the 357 70-GS genomic low-risk patients was 94.2% (95% CI 91.2-96.2) and 89.1% for the 249 genomic high-risk patients (95% CI 84.3-92.4). Of the low-risk patients 3% had received chemotherapy compared to 80% of the high-risk patients. For the subgroups based on the pre-test oncologists' advice (no chemotherapy/chemotherapy/unsure) there were no clinically relevant differences in DMFS (89.8, 93.2 and 92.0%, respectively), while comparable proportions of patients had received chemotherapy. CONCLUSIONS: In patients with early-stage ER+ breast cancer with a disputable chemotherapy indication it is sensible to deploy the 70-GS to better select patients for adjuvant chemotherapy.

De-escalation of axillary treatment in the event of a positive sentinel lymph node biopsy in cT1-2 N0 breast cancer treated with mastectomy: nationwide registry study (BOOG 2013-07).

BACKGROUND: Trials have demonstrated the safety of omitting completion axillary lymph node dissection in patients with cT1-2 N0 breast cancer operated with breast-conserving surgery who have limited metastatic burden in the sentinel lymph node. The aim of this registry study was to provide insight into the oncological safety of omitting completion axillary treatment in patients operated with mastectomy who have limited-volume sentinel lymph node metastasis. METHODS: Women diagnosed in 2013-2014 with unilateral cT1-2 N0 breast cancer treated with mastectomy, with one to three sentinel lymph node metastases (pN1mi-pN1a), were identified from the Netherlands Cancer Registry, and classified by axillary treatment: no completion axillary treatment, completion axillary lymph node dissection, regional radiotherapy, or completion axillary lymph node dissection followed by regional radiotherapy. The primary endpoint was 5-year regional recurrence rate. Secondary endpoints included recurrence-free interval and overall survival, among others. RESULTS: In total, 1090 patients were included (no completion axillary treatment, 219 (20.1%); completion axillary lymph node dissection, 437 (40.1%); regional radiotherapy, 327 (30.0%); completion axillary lymph node dissection and regional radiotherapy, 107 (9.8%)). Patients in the group without completion axillary treatment had more favourable tumour characteristics and were older. The overall 5-year regional recurrence rate was 1.3%, and did not differ significantly between the groups. The recurrence-free interval was also comparable among groups. The group of patients who did not undergo completion axillary treatment had statistically significantly worse 5-year overall survival, owing to a higher percentage of non-cancer deaths. CONCLUSION: In this registry study of patients with cT1-2 N0 breast cancer treated with mastectomy, with low-volume sentinel lymph node metastasis, the 5-year regional recurrence rate was low and comparable between patients with and without completion axillary treatment.

Inequalities in the omission of axillary dissection in sentinel lymph node positive patients in the Netherlands: Innovative hospitals are early adopters of a de-escalating approach.

During the last decade completion axillary lymph node dissection (cALND) was gradually omitted in sentinel lymph node positive (SLN+) breast cancer patients. However, adoption varies among hospitals. We analyzed factors associated with the omission of cALND in all Dutch SLN+ patients. As one of the focus hospital-related factors we defined "innovative" as the percentage of gene-expression profile (GEP) deployment within the indicated group of patients per hospital as a proxy for early adoption of innovations. cT1-2N0M0 SLN+ patients treated between 2011 and 2018 were selected from the Netherlands Cancer Registry. Hospitals were defined to be innovative based on their GEP use. Multivariable logistic regression (MLR) was performed to assess the relationship between innovative capacity, patient-, treatment- and hospital-related characteristics and cALND performance. 14 317 patients were included. Treatment in a hospital with high innovative capacity was associated with a lower probability of receiving cALND (OR 0.69, OR 0.46 and OR 0.35 in modestly, fairly and very innovative, respectively). Other factors associated with a lower probability of receiving a cALND were age 70 and 79 years and ≥79 years (ORs 0.59 [95% CI: 0.50-0.68] and 0.21 [95% CI: 0.17-0.26]) and treatment in an academic hospital (OR 0.41 [95% CI: 0.33-0.51]). Factors associated with an increased probability of undergoing cALND were HR-/HER2- tumors (OR 1.46 [95% CI: 1.19-1.80]), macrometastatic lymph node involvement (OR 6.37 [95% CI: 5.70-7.13]) and mastectomy (OR 4.57 [95% CI: 4.09-5.10]). Patients treated in a hospital that early adopted innovations were less likely to receive cALND. Our findings endorse the need for studies on barriers and facilitators of implementing innovations.

Health-related Quality of Life of Patients With Non-Intra-abdominal Desmoid-Type Fibromatosis During Active Surveillance: Results of a Prospective Observational Study.

OBJECTIVE: To examine the impact of an active surveillance (AS) approach on the health-related quality of life (HRQoL) of patients with desmoid-type fibromatosis (DTF). BACKGROUND DATA: AS is recommended as initial approach in DTF patients. AS might however negatively affect HRQoL due to physical symptoms or stress and anxiety. METHODS: In a prospective observational study, the GRAFITI trial (NTR4714), DTF patients were followed during an initial AS approach for 3 years. HRQoL was assessed by the EORTC QLQ-C30 at baseline, 6, 12 and 24-month follow-up. Patients who completed questionnaires at≥1-time point were included in this analysis of the secondary endpoint. A multivariable linear mixed-effects model with random intercept was conducted to assess trends of HRQoL scores over time and to explore the effect of treatment strategy on HRQoL. RESULTS: All 105 patients enrolled in the GRAFITI trial were eligible for the HRQoL analyses. During 24-month follow-up, 75 patients (71%) continued AS and 30 patients (29%) started an active treatment (AT). DTF patients who continued AS demonstrated relatively stable HRQoL scores during follow-up. HRQoL scores of patients who started AT worsened compared to patients who continued AS, although no significant changes in HRQoL score over time were found in the mixed-model analyses. Overall, DTF patients who started AT scored significantly worse on pain (ß=10.08, P =0.039) compared to patients who continued AS. CONCLUSIONS: An initial AS approach did not impair HRQoL of DTF patients who continued AS over time, therefore providing further support for AS as the frontline approach in DTF patients. Longitudinal assessment of HRQoL should be part of clinical follow-up to identify patients who may need a change in treatment strategy.

A Nationwide Prospective Clinical Trial on Active Surveillance in Patients With Non-intraabdominal Desmoid-type Fibromatosis: The GRAFITI Trial.

OBJECTIVE: To assess tumor behavior and the efficacy of active surveillance (AS) in patients with desmoid-type fibromatosis (DTF). SUMMARY OF BACKGROUND DATA: AS is recommended as initial management for DTF patients. Prospective data regarding the results of AS are lacking. METHODS: In this multicenter prospective cohort study (NTR4714), adult patients with non-intraabdominal DTF were followed during an initial AS approach for 3 years. Tumor behavior was evaluated according to Response Evaluation Criteria in Solid Tumors. Cumulative incidence of the start of an active treatment and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Factors predictive for start of active treatment were assessed by Cox regression analyses. RESULTS: A total of 105 patients started with AS. Median tumor size at baseline was 4.1cm (interquartile range 3.0-6.6). Fifty-seven patients had a T41A CTNNB1 mutation; 14 patients a S45F CTNNB1 mutation. At 3 years, cumulative incidence of the start of active treatment was 30% (95% confidence interval [CI] 21-39) and PFS was 58% (95% CI 49-69). Median time to start active treatment and PFS were not reached at a median follow-up of 33.7 months. During AS, 32% of patients had stable disease, 28% regressed, and 40% demonstrated initial progression. Larger tumor size (≥5 cm; hazard ratio = 2.38 [95% CI 1.15-4.90]) and S45F mutation (hazard ratio = 6.24 [95% CI 1.92-20.30]) were associated with the start of active treatment. CONCLUSIONS: The majority DTF patients undergoing AS do not need an active treatment and experience stable or regressive disease, even after initial progression. Knowledge about the natural behavior of DTF will help to tailor the follow-up schedule to the individual patient.

Physical Function and Physical Activity in Older Breast Cancer Survivors: 5-Year Follow-Up from the Climb Every Mountain Study.

BACKGROUND: A decline in physical activity and the ability to perform activities of daily living (ADL) and instrumental activities of daily living (IADL) could interfere with independent living and quality of life in older patients, but may be prevented with tailored interventions. The aim of the current study was to assess changes in physical activity and ADL/IADL in the first 5 years after breast cancer diagnosis in a real-world cohort of older patients and to identify factors associated with physical decline. METHODS: Patients aged ≥70 years with in situ or stages I-III breast cancer were included in the prospective Climb Every Mountain cohort study. Linear mixed models were used to assess physical activity (according to Metabolic Equivalent of Task (MET) hours per week) and ADL/IADL (according to the Groningen Activity Restriction Scale (GARS)) over time. Secondly, the association with geriatric characteristics, treatment, quality of life, depression, apathy, and loneliness was analyzed. RESULTS: A total of 239 patients were included. Physical activity and ADL/IADL changed in the first 5 years after diagnosis (mean change from baseline -11.6 and +4.2, respectively). Geriatric characteristics at baseline were strongly associated with longitudinal change in physical activity and ADL/IADL, whereas breast cancer treatment was not. A better quality of life was associated with better physical activity and preservation of ADL/IADL, while depression and loneliness were negatively associated with these outcomes. DISCUSSION: Geriatric characteristics, loneliness, and depressive symptoms were associated with physical decline in older patients with breast cancer, while breast cancer treatment was not.

Radiofrequency localization of nonpalpable breast cancer in a multicentre prospective cohort study: feasibility, clinical acceptability, and safety.

PURPOSE: In breast conserving surgery, accurate lesion localization is essential for obtaining adequate surgical margins. Preoperative wire localization (WL) and radioactive seed localization (RSL) are widely accepted methods to guide surgical excision of nonpalpable breast lesions but are limited by logistical challenges, migration issues, and legislative complexities. Radiofrequency identification (RFID) technology may offer a viable alternative. The purpose of this study was to evaluate the feasibility, clinical acceptability, and safety of RFID surgical guidance for localization of nonpalpable breast cancer. METHODS: In a prospective multicentre cohort study, the first 100 RFID localization procedures were included. The primary outcome was the percentage of clear resection margins and re-excision rate. Secondary outcomes included procedure details, user experience, learningcurve, and adverse events. RESULTS: Between April 2019 and May 2021, 100 women underwent RFID guided breast conserving surgery. Clear resection margins were obtained in 89 out of 96 included patients (92.7%), re-excision was indicated in three patients (3.1%). Radiologists reported difficulties with the placement of the RFID tag, partially related to the relatively large needle-applicator (12-gauge). This led to the premature termination of the study in the hospital using RSL as regular care. The radiologist experience was improved after a manufacturer modification of the needle-applicator. Surgical localization involved a low learning curve. Adverse events (n = 33) included dislocation of the marker during insertion (8%) and hematomas (9%). The majority of adverse events (85%) occurred using the first-generation needle-applicator. CONCLUSION: RFID technology is a potential alternative for non-radioactive and non-wire localization of nonpalpable breast lesions.

Trends of Axillary Treatment in Sentinel Node-Positive Breast Cancer Patients Undergoing Mastectomy.

BACKGROUND: The ACOSOG-Z0011- and the AMAROS-trial obviated the need for axillary surgery in most sentinel node-positive (SLN+) breast cancer patients undergoing breast-conserving surgery (BCS). Data for patients who undergo mastectomy is scarce. The purpose of this study was to investigate patterns of axillary treatment in SLN+ patients treated by mastectomy in the years after the publication of landmark studies regarding axillary treatment in SLN+ breast cancer patients undergoing BCS. METHODS: This was a population-based study in cT1-3N0M0 breast cancer patients treated by mastectomy and staged as SLN+ between 2009 and 2018. The performance of an axillary lymph node dissection (ALND) and/or administration of postmastectomy radiotherapy (PMRT) were primary outcomes and were studied over time. RESULTS: The study included 10,633 patients. The frequency of ALND performance decreased from 78% in 2009 to 10% in 2018, whereas PMRT increased from 4 to 49% (P < 0.001). In ≥N1a patients, ALND performance decreased from 93 to 20%, whereas PMRT increased to 70% (P < 0.001). In N1mi and N0itc patients, ALND was abandoned during the study period, whereas PMRT increased to 38% and 13% respectively (P < 0.001), respectively. Age, tumor subtype, N-stage, and hospital type affected the likelihood that patients underwent ALND. CONCLUSIONS: In this study in SLN+ breast cancer patients undergoing mastectomy, use of ALND decreased drastically over time. By the end of 2018 most ≥N1a patients received PMRT as the only adjuvant axillary treatment, whereas the majority of N1mi and N0itc patients received no additional treatment.

De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study.

BACKGROUND: Primary chemotherapy in breast cancer poses a dilemma with regard to adjuvant locoregional radiotherapy, as guidelines for locoregional radiotherapy were originally based on pathology results of primary surgery. We aimed to evaluate the oncological safety of de-escalated locoregional radiotherapy in patients with cT1-2N1 breast cancer treated with primary chemotherapy, according to a predefined, consensus-based study guideline. METHODS: In this prospective registry study (RAPCHEM, BOOG 2010-03), patients referred to one of 17 participating radiation oncology centres in the Netherlands between Jan 1, 2011, and Jan 1, 2015, with cT1-2N1 breast cancer (one to three suspicious nodes on imaging before primary chemotherapy, of which at least one had been pathologically confirmed), and who were treated with primary chemotherapy and surgery of the breast and axilla were included in the study. The study guideline comprised three risk groups for locoregional recurrence, with corresponding locoregional radiotherapy recommendations: no chest wall radiotherapy and no regional radiotherapy in the low-risk group, only local radiotherapy in the intermediate-risk group, and locoregional radiotherapy in the high-risk group. Radiotherapy consisted of a biologically equivalent dose of 25 fractions of 2 Gy, with or without a boost. During the study period, the generally applied radiotherapy technique in the Netherlands was forward-planned or inverse-planned intensity modulated radiotherapy. 5-year follow-up was assessed, taking into account adherence to the study guideline, with locoregional recurrence rate as primary endpoint. We hypothesised that 5-year locoregional recurrence rate would be less than 4% (upper-limit 95% CI 7·8%). This study was registered at ClinicalTrials.gov, NCT01279304, and is completed. FINDINGS: 838 patients were eligible for 5-year follow-up analyses: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 5-year locoregional recurrence rate in all patients was 2·2% (95% CI 1·4-3·4). The 5-year locoregional recurrence rate was 2·1% (0·9-4·3) in the low-risk group, 2·2% (1·0-4·1) in the intermediate-risk group, and 2·3% (0·8-5·5) in the high-risk group. If the study guideline was followed, the locoregional recurrence rate was 2·3% (0·8-5·3) for the low-risk group, 1·0% (0·2-3·4) for the intermediate-risk group, and 1·4% (0·3-4·5) for the high-risk group. INTERPRETATION: In this study, the 5-year locoregional recurrence rate was less than 4%, which supports our hypothesis that it is oncologically safe to de-escalate locoregional radiotherapy based on locoregional recurrence risk, in selected patients with cT1-2N1 breast cancer treated with primary chemotherapy, according to this predefined, consensus-based study guideline. FUNDING: Dutch Cancer Society. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

The impact of the COVID-19 pandemic on perceived access to health care and preferences for health care provision in individuals (being) treated for breast cancer.

PURPOSE: To evaluate perceived access to health care and preferences for health care provision among patients (being) treated for breast cancer during the COVID-19 pandemic. METHODS: Longitudinal study within the prospective, multicenter UMBRELLA cohort of patients (being) treated for breast cancer. All cohort participants enrolled in UMBRELLA between October 2013 and November 2020 were sent a COVID-19-specific survey during the first and second wave of the COVID-19 pandemic, i.e., April 2020 and November 2020, respectively. RESULTS: In total, 1106 (69.3%) and 822 (50.9%) cohort participants completed the survey in the first and second wave, respectively. The proportion of patients experiencing that their treatment or follow-up care was affected due to COVID-19 decreased from 28.4% (n = 198) in April 2020 to 14.8% (n = 103) in November 2020. Throughout the pandemic, one or more hospital consultations were postponed in 10.0% (n = 82) of all patients and changed into a teleconsultation in 23.1% (n = 190). The proportion of patients who experienced a higher threshold to contact their general practitioner due to COVID-19 decreased from 29.9% (n = 204) in the first wave to 20.8% (n = 145) in the second wave. In-person consultations remained most preferred in 35.2% (n = 289) of all patients. Nearly half of all patients (48.3%, n = 396) indicated that telehealth would be a useful alternative for in-person consultations in future. CONCLUSION: Perceived access to health care has improved substantially throughout the pandemic. Digital care is well received by patients (being) treated for breast cancer.

Discontinuation of adjuvant endocrine therapy and impact on quality of life and functional status in older patients with breast cancer.

PURPOSE: Side effects are the main reason for discontinuation of adjuvant endocrine therapy in older adults. The aim of this study was to examine geriatric predictors of treatment discontinuation of adjuvant endocrine therapy within the first 2 years after initiation, and to study the association between early discontinuation and functional status and quality of life (QoL). METHODS: Patients aged ≥ 70 years with stage I-III breast cancer who received adjuvant endocrine therapy were included. The primary endpoint was discontinuation of endocrine therapy within 2 years. Risk factors for discontinuation were assessed using univariate logistic regression models. Linear mixed models were used to assess QoL and functional status over time. RESULTS: Overall, 258 patients were included, of whom 36% discontinued therapy within 2 years after initiation. No geriatric predictive factors for treatment discontinuation were found. Tumour stage was inversely associated with early discontinuation. Patients who discontinued had a worse breast cancer-specific QoL (b = - 4.37; 95% CI - 7.96 to - 0.78; p = 0.017) over the first 2 years, in particular on the future perspective subscale (b = - 11.10; 95% CI - 18.80 to - 3.40; p = 0.005), which did not recover after discontinuation. Treatment discontinuation was not associated with functional improvement. CONCLUSION: A large proportion of older patients discontinue adjuvant endocrine treatment within 2 years after initiation, but geriatric characteristics are not predictive of early discontinuation of treatment. Discontinuation of adjuvant endocrine therapy did not positively affect QoL and functional status, which implies that the observed poorer QoL in this group is probably not caused by adverse effects of endocrine therapy.

A multicenter prospective cohort study to evaluate feasibility of radio-frequency identification surgical guidance for nonpalpable breast lesions: design and rationale of the RFID Localizer 1 Trial.

BACKGROUND: Breast cancer screening and improving imaging techniques have led to an increase in the detection rate of early, nonpalpable breast cancers. For early breast cancer, breast conserving surgery is an effective and safe treatment. Accurate intraoperative lesion localization during breast conserving surgery is essential for adequate surgical margins while sparing surrounding healthy tissue to achieve optimal cosmesis. Preoperative wire localization and radioactive seed localization are accepted standard methods to guide surgical excision of nonpalpable breast lesions. However, these techniques present significant limitations. Radiofrequency identification (RFID) technology offers a new, nonradioactive method for localizing nonpalpable breast lesions in patients undergoing breast conserving surgery. This study aims to evaluate the feasibility of RFID surgical guidance for nonpalpable breast lesions. METHODS: This multicenter prospective cohort study was approved by the Institutional Review Board of the University Medical Center Utrecht. Written informed consent is obtained from all participants. Women with nonpalpable, histologically proven in situ or invasive breast cancer, who can undergo breast conserving surgery with RFID localization are considered eligible for participation. An RFID tag is placed under ultrasound guidance, up to 30 days preoperatively. The surgeon localizes the RFID tag with a radiofrequency reader that provides audible and visual real-time surgical guidance. The primary study outcome is the percentage of irradical excisions and reexcision rate, which will be compared to standards of the National Breast Cancer Organisation Netherlands (NABON)(≤ 15% irradical excisions of invasive carcinomas). Secondary outcomes include user acceptability/experiences, learning curve, duration and ease of the placement- and surgical procedure and adverse events. DISCUSSION: This study evaluates the feasibility of RFID surgical guidance for nonpalpable breast lesions. Results may have implications for the future localization techniques in women with nonpalpable breast cancer undergoing breast conserving surgery. TRIAL REGISTRATION: Netherlands National Trial Register, NL8019 , registered on September 12th 2019.

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.

(Ex-)breast cancer patients with (pre-existing) symptoms of anxiety and/or depression experience higher barriers to contact health care providers during the COVID-19 pandemic.

PURPOSE: To identify factors associated with (perceived) access to health care among (ex-)breast cancer patients during the COVID-19 pandemic. METHODS: Cross-sectional study within a large prospective, multicenter cohort of (ex-)breast cancer patients, i.e., UMBRELLA. All participants enrolled in the UMBRELLA cohort between October 2013 and April 2020 were sent a COVID-19-specific survey, including the Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS: In total, 1051 (66.0%) participants completed the survey. During COVID-19, 284 (27.0%) participants reported clinically relevant increased levels of anxiety and/or depression, i.e., total HADS score ≥ 12. Participants with anxiety and/or depression reported statistically significant higher barriers to contact their general practitioner (47.5% vs. 25.0%, resp.) and breast cancer physicians (26.8% vs. 11.2%, resp.) compared to participants without these symptoms. In addition, a higher proportion of participants with anxiety and/or depression reported that their current treatment or (after)care was affected by COVID-19 compared to those without these symptoms (32.7% vs. 20.5%, resp.). Factors independently associated with symptoms of anxiety and/or depression during COVID-19 were pre-existent anxiety (OR 6.1, 95% CI 4.1-9.2) or depression (OR 6.0, 95% CI 3.5-10.2). CONCLUSION: During the COVID-19 pandemic, (ex-)breast cancer patients with symptoms of anxiety and/or depression experience higher barriers to contact health care providers. Also, they more often report that their health care was affected by COVID-19. Risk factors for anxiety and/or depression during COVID-19 are pre-existent symptoms of anxiety or depression. Extra attention-including mental health support-is needed for this group.

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.

Patients' perceptions of 70-gene signature testing: commonly changing the initial inclination to undergo or forego chemotherapy and reducing decisional conflict.

PURPOSE: Little is known about the impact of 70-gene signature (70-GS) use on patients' chemotherapy decision-making. The primary aim of this study was to evaluate the impact of 70-GS use on patients' decisions to undergo chemotherapy. The perceived decision conflict during decision-making was a secondary objective of the study. METHODS: Patients operated for estrogen receptor positive early breast cancer were asked to fill out a questionnaire probing their inclination to undergo chemotherapy before deployment of the 70-GS test. After disclosure of the 70-GS result patients were asked about their decision regarding chemotherapy. Patients' decisional conflict was measured using the 16-item decisional conflict scale (DCS); scores < 25 are associated with a persuaded decision while a score > 37.5 implies that one feels unsure about a choice. RESULTS: Between January 1th 2017 and December 31th 2018, 106 patients completed both questionnaires. Before deployment of the 70-GS, 58% of patients (n = 62) formulated a clear treatment preference, of whom 21 patients (34%) changed their opinion on treatment with chemotherapy following the 70-GS. The final decision regarding chemotherapy was in line with the 70-GS result in 90% of patients. The percentage of patients who felt unsure about their preference to be treated with chemotherapy decreased from 42 to 5% after disclosure of the 70-GS. The mean total DCS significantly decreased from pre-test to post-test from 35 to 23, irrespective of the risk estimate (p < 0.001). CONCLUSION: Deployment of the 70-GS changed patients' inclination to undergo adjuvant chemotherapy in one third of patients and decreased patients' decisional conflict.

Quantifying the Mitigating Effects of Whole-Breast Radiotherapy and Systemic Treatments on Regional Recurrence Incidence Among Breast Cancer Patients.

BACKGROUND: Despite the potential for residual lymph node metastases after a negative or positive sentinel lymph node biopsy (SLNB), breast cancer patients rarely experience regional recurrences (RRs). This study aimed to quantify the effects of nonsurgical treatments on RR incidence among SLNB-negative (SLNB N0) breast cancer patients. METHODS: All primary SLNB N0-staged breast cancer patients with a diagnosis between 2005 and 2008 and 5-year follow-up data on recurrences were selected from the Netherlands Cancer Registry. The cumulative incidence function (CIF) for RR was calculated as the first event at 5 years, taking into account any other first-event (local or distant recurrence, contralateral breast cancer, or death) as competing risk. Cox regression analysis was used to model the cause-specific hazard of RR developing as the first event to quantify the effect of adjuvant systemic therapy and whole-breast radiotherapy (RT) on RR incidence at 5 years. RESULTS: The study included 13,512 patients. Of these patients, 162 experienced an RR. The CIF of RR at 5 years was 1.3% (95% confidence interval [CI], 1.1-1.5%), whereas the CIFs for death and other events were 4.4% and 9.5%, respectively. Cox regression analysis showed hazard ratios (HRs) of 0.46 (95% CI 0.33-0.64), 0.31 (95% CI 0.18-0.55), and 0.40 (95% CI 0.24-0.67) respectively for patients treated by RT as a routine part of breast-conserving therapy (BCT), chemotherapy, and hormonal therapy. CONCLUSION: RT as routine part of BCT, chemotherapy, and hormonal therapy independently exerted a mitigating effect on the risk for the development of RR. The three methods at least halved the risk.

Assessment of tumour proliferation by use of the mitotic activity index, and Ki67 and phosphohistone H3 expression, in early-stage luminal breast cancer.

AIMS: Phosphohistone H3 (PhH3) has been proposed as a novel proliferation marker in breast cancer. This study compares the interobserver agreement for assessment of the mitotic activity index (MAI), Ki67 expression, and PhH3 in a cohort of oestrogen receptor (ER)-positive breast cancer patients. METHODS AND RESULTS: Tumour samples of 159 luminal breast cancer patients were collected. MAI and PhH3 scores were assessed by three breast cancer pathologists. Ki67 scores were assessed separately by two of the three pathologists. PhH3-positive cells were counted in an area of 2 mm2 , with a threshold of ≥13 positive cells being used to discriminate between low-proliferative and high-proliferative tumours. Ki67 expression was assessed with the global scoring method. Ki67 percentages of <20% were considered to be low. The intraclass correlation coefficient (ICC) and Cohen's κ statistics were used to evaluate interobserver agreement. The impact on histological grading of replacing the MAI with PhH3 was assessed. Counting PhH3-positive cells was highly reproducible among all three observers (ICC of 0.86). The κ scores for the categorical PhH3 count (κ = 0.78, κ = 0.68, and κ = 0.80) reflected substantial agreement among all observers, whereas agreement for the MAI (κ = 0.38, κ = 0.52, and κ = 0.26) and Ki67 (κ = 0.55) was fair to moderate. When PhH3 was used to determine the histological grade, agreement in grading increased (PhH3, κ = 0.52, κ = 0.48, and κ = 0.52; MAI, κ = 0.43, κ = 0.35, and κ = 0.32), and the proportion of grade III tumours increased (14%, 18%, and 27%). CONCLUSION: PhH3 seems to outperform Ki67 and the MAI as a reproducible means to measure tumour proliferation in luminal-type breast cancer. Variation in the assessment of histological grade might be reduced by using PhH3, but would result in an increase in the proportion of high-grade cancers.

Breast-Contour-Preserving Procedure as a Multidisciplinary Parameter of Esthetic Outcome in Breast Cancer Treatment in The Netherlands.

BACKGROUND: The rate of breast-conserving surgery (BCS) is used as an esthetic outcome parameter, while other treatments contribute also, such as neoadjuvant chemotherapy (NAC) enabling BCS or immediate breast reconstruction (IBR). This study explores these efforts to preserve the patient's breast contour. PATIENTS AND METHODS: All patients who underwent surgery for invasive breast cancer in The Netherlands between January 2011 and December 2015 were selected from the Dutch national breast cancer audit (n = 61,309). The breast-contour-preserving procedures (BCPP) rate was defined as the rate of primary BCS, BCS after NAC, or mastectomy with IBR. BCPP rates were calculated and compared by year of diagnosis, age categories, and individual hospitals. RESULTS: The rate of primary BCS remained stable (53%) while the BCPP rate increased from 63% in 2011 to 71% in 2015 due to an increase in patients receiving BCS after NAC and mastectomy with IBR. Primary BCS rates increased with age (from 17% in patients aged < 30 years to 63% in patients aged 60-69 years), while the proportion of patients undergoing mastectomy with IBR decreased from 44% in patients < 30 years to 1% in patients ≥ 70 years. The BCPP rate was similar for all age groups except for patients > 70 years. BCPP rates varied between the different hospitals in The Netherlands, ranging from 47 to 88%. CONCLUSIONS: The chance of preserving the breast contour for patients with breast cancer has increased substantially over recent years. BCPP provides a comprehensive parameter of esthetic outcome of breast cancer surgery.