Clinical implications of non-breast cancer related findings on FDG-PET/CT scan prior to neoadjuvant chemotherapy in patients with breast cancer.

PURPOSE: Breast cancer (BC) patients undergoing FDG-PET/CT scans for neoadjuvant chemotherapy (NAC) may have additional non-BC related findings. The aim of this study is to describe the clinical implications of these findings. METHODS: We included BC patients who underwent an FDG-PET/CT scan in our institute between 2011-2020 prior to NAC. We focused on patients with an additional non-BC related finding (i.e. BC metastases were excluded) for which diagnostic work-up was performed. Information about the diagnostic work-up and the clinical consequences was retrospectively gathered. A revision of all FDG-PET/CT scans was conducted by an independent physician to assess the suspicion level of the additional findings. RESULTS: Of the 1337 patients who underwent FDG-PET/CT, 202 patients (15%) had an non-BC related additional finding for which diagnostic work-up was conducted, resulting in 318 examinations during the first year. The non-BC related findings were mostly detected in the endocrine region (26%), gastro-intestinal region (16%), or the lungs (15%). Seventeen patients (17/202: 8%, 17/1337: 1.3%) had a second primary malignancy. Only 8 patients (8/202: 4%, 8/1337: 0.6%) had a finding that was considered more prognosis-determining than their BC disease. When revising all FDG-PET/CT scans, 57 (202/57: 28%) of the patients had an additional finding categorized as low suspicious, suggesting no indication for diagnostic work-up. CONCLUSION: FDG-PET/CT scans used for dissemination imaging in BC patients detect a high number of non-BC related additional findings, often clinically irrelevant and causing a large amount of unnecessary work-up. However, in 8% of the patients undergoing diagnostic work-up for an additional finding, a second primary malignancy was detected, warranting diagnostic attention in selected patients.

Recurrence of breast cancer after reconstruction with macro-textured silicone breast implants: A retrospective cohort study.

BACKGROUND: Recently, old concerns linking silicone breast implants (SBIs) with breast cancer have resurfaced. These concerns apply specifically to the risk of breast cancer recurrence in patients who received breast reconstructions with macro-textured SBIs. In this study, we investigated the effect of breast reconstruction with macro-textured SBIs on long-term oncologic outcomes of breast cancer patients. MATERIALS AND METHODS: We conducted a retrospective cohort study in two large cancer centres in the Netherlands. Patients who had been treated for primary breast cancer between January 1st 2000 and December 31st 2015 were included. Data on treatment and oncologic outcomes were obtained from prospectively maintained institutional and nationwide registries. Patient files were reviewed manually to complement missing information. Missing data was accounted for by multiple imputation by chained equations (MICE). Reconstruction with a macro-textured SBI was analysed as a time-dependent variable. The main outcomes of interest were locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). Hazard Ratios (HRs) were estimated using multivariable Cox proportional hazard models. RESULTS: Of the 4,695 women who were eligible for inclusion, 2,393 had undergone mastectomy. Of these women, 1,187 (25%) had received breast reconstruction with a macro-textured SBI. Mean follow-up time was 11.5 (SD, 5.0) years. Compared with women who had undergone a simple mastectomy or autologous breast reconstruction, women with an implant-based reconstruction did not differ significantly in LRRFS or DMFS after accounting for various confounding factors (HR 1.27 [95% CI 0.93 - 1.72] and HR 0.94 [95% CI 0.74 - 1.20], respectively). Sensitivity analysis in complete cases of patients and varies subgroup analyses yielded similar results. CONCLUSION: Reassuringly, in this multi-centre cohort study no difference was found in long-term oncologic outcomes between women who had received breast reconstruction with a macro-textured SBI and women who had undergone a simple mastectomy or autologous breast reconstruction.

Resection Ratios and Tumor Eccentricity in Breast-Conserving Surgery Specimens for Surgical Accuracy Assessment.

This study aims to evaluate several defined specimen parameters that would allow to determine the surgical accuracy of breast-conserving surgeries (BCS) in a representative population of patients. These specimen parameters could be used to compare surgical accuracy when using novel technologies for intra-operative BCS guidance in the future. Different specimen parameters were determined among 100 BCS patients, including the ratio of specimen volume to tumor volume (resection ratio) with different optimal margin widths (0 mm, 1 mm, 2 mm, and 10 mm). Furthermore, the tumor eccentricity [maximum tumor-margin distance - minimum tumor-margin distance] and the relative tumor eccentricity [tumor eccentricity ÷ pathological tumor diameter] were determined. Different patient subgroups were compared using Wilcoxon rank sum tests. When using a surgical margin width of 0 mm, 1 mm, 2 mm, and 10 mm, on average, 19.16 (IQR 44.36), 9.94 (IQR 18.09), 6.06 (IQR 9.69) and 1.35 (IQR 1.78) times the ideal resection volume was excised, respectively. The median tumor eccentricity among the entire patient population was 11.29 mm (SD = 3.99) and the median relative tumor eccentricity was 0.66 (SD = 2.22). Resection ratios based on different optimal margin widths (0 mm, 1 mm, 2 mm, and 10 mm) and the (relative) tumor eccentricity could be valuable outcome measures to evaluate the surgical accuracy of novel technologies for intra-operative BCS guidance.

Margin assessment during breast conserving surgery using diffuse reflectance spectroscopy.

Significance: During breast-conserving surgeries, it is essential to evaluate the resection margins (edges of breast specimen) to determine whether the tumor has been removed completely. In current surgical practice, there are no methods available to aid in accurate real-time margin evaluation. Aim: In this study, we investigated the diagnostic accuracy of diffuse reflectance spectroscopy (DRS) combined with tissue classification models in discriminating tumorous tissue from healthy tissue up to 2 mm in depth on the actual resection margin of in vivo breast tissue. Approach: We collected an extensive dataset of DRS measurements on ex vivo breast tissue and in vivo breast tissue, which we used to develop different classification models for tissue classification. Next, these models were used in vivo to evaluate the performance of DRS for tissue discrimination during breast conserving surgery. We investigated which training strategy yielded optimum results for the classification model with the highest performance. Results: We achieved a Matthews correlation coefficient of 0.76, a sensitivity of 96.7% (95% CI 95.6% to 98.2%), a specificity of 90.6% (95% CI 86.3% to 97.9%) and an area under the curve of 0.98 by training the optimum model on a combination of ex vivo and in vivo DRS data. Conclusions: DRS allows real-time margin assessment with a high sensitivity and specificity during breast-conserving surgeries.

Radiological, pathological and surgical outcomes after neoadjuvant endocrine treatment in patients with ER-positive/HER2-negative breast cancer with a clinical high risk and a low-risk 70-gene signature.

OBJECTIVE: This study aims to evaluate the response to and surgical benefits of neoadjuvant endocrine therapy (NET) in ER+/HER2-breast cancer patients who are clinically high risk, but genomic low risk according to the 70-gene signature (MammaPrint). METHODS: Patients with ER+/HER2-invasive breast cancer with a clinical high risk according to MINDACT, who had a genomic low risk according to the 70-gene signature and were treated with NET between 2015 and 2023 in our center, were retrospectively analyzed. RECIST 1.1 criteria were used to assess radiological response using MRI or ultrasound. Surgical specimens were evaluated to assess pathological response. Two breast cancer surgeons independently scored the eligibility of breast conserving therapy (BCS) pre- and post- NET. RESULTS: Of 72 included patients, 23 were premenopausal (100% started with tamoxifen of which 4 also received OFS) and 49 were postmenopausal (98% started with an aromatase inhibitor). Overall, 8 (11%) showed radiological complete response. Only 1 (1.4%) patient had a pathological complete response (RCB-0) and 68 (94.4%) had a pathological partial response (RCB-1 or RCB-2). Among the 26 patients initially considered for mastectomy, 14 (53.8%) underwent successful BCS. In all 20 clinical node-positive patients, a marked axillary lymph node was removed to assess response. Four out of 20 (20%) patients had a pathological complete response of the axilla. CONCLUSION: The study showed that a subgroup of patients with a clinical high risk and a genomic low risk ER+/HER2-breast cancer benefits from NET resulting in BCS instead of a mastectomy. Additionally, NET may enable de-escalation in axillary treatment.

Strategies to increase survey participation: A randomized controlled study in a population of breast cancer survivors.

BACKGROUND: Data collection by mailing questionnaires to the study population is one of the main research methods in epidemiologic studies. As participation rates are decreasing, easy-to-implement and cost-effective strategies to increase survey participation are needed. In this study, we tested the effect of a pragmatic combination of evidence-based interventions. METHODS: We conducted a two-armed randomized controlled trial, nested in a cohort of breast cancer survivors (n = 1000) in the setting of a health outcomes survey. The intervention arm received a postal pre-notification, a non-monetary incentive (ballpoint with the study logo) and an alternative invitation letter in which several lay-out and textual adjustments were implemented according to behavioural science techniques. The alternative invitation letter also contained a QR-code through which an information video about the study could be accessed. The control arm was invited according to standard practice. Participants had the option to fill-out a questionnaire either on paper or online. A questionnaire with more than 50% of the questions answered classified as participation. RESULTS: Overall participation rate was 62.9%. No significant difference in participation rate was observed between intervention and control arm (64.5% vs 61.3%, Risk Ratio (RR) 1.05, 95% CI [0.96 - 1.16]). Older age at study (>65 vs <51 years), and high socio-economic status (highest vs lowest quartile) were associated with higher participation rates (RR 1.30, 95% CI [1.07 - 1.57] and 1.24, 95% CI [1.09 - 1.42] respectively). In-situ carcinoma compared to invasive cancer and longer interval since treatment were associated with lower participation (RR 0.86, 95% CI [0.74 - 0.99] and RR 0.92, 95% CI [0.87 - 0.99] per 5 year increase, respectively). CONCLUSION: Overall, the combination of four interventions tested in this study did not improve survey participation among breast cancer survivors. The overall participation rate was relatively high, possibly due to the study population of cancer survivors.

MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.

Systematic review of targeted axillary dissection in node-positive breast cancer treated with neoadjuvant systemic therapy: variation in type of marker and timing of placement.

BACKGROUND: In node-positive (cN+) breast cancer treated with neoadjuvant systemic therapy, combining sentinel lymph node biopsy and targeted lymph node excision, that is targeted axillary dissection, increases accuracy. Targeted axillary dissection procedures differ in terms of the targeted lymph node excision technique. This systematic review aimed to provide an overview of targeted axillary dissection procedures regarding definitive marker type and timing of placement: before neoadjuvant systemic therapy (1-step procedure) or after neoadjuvant systemic therapy adjacent to a clip placed before the neoadjuvant therapy (2-step procedure). METHODS: PubMed and Embase were searched, to 4 July 2023, for RCTs, cohort studies, and case-control studies with at least 25 patients. Studies of targeted lymph node excision only (without sentinel lymph node biopsy), or where intraoperative localization of the targeted lymph node was not attempted, were excluded. For qualitative synthesis, studies were grouped by definitive marker and timing of placement. The targeted lymph node identification rate was reported. Study quality was assessed using a National Institutes of Health quality assessment tool. RESULTS: Of 277 unique records, 51 studies with a total of 4512 patients were included. Six definitive markers were identified: wire, 125I-labelled seed, 99mTc, (electro)magnetic/radiofrequency markers, black ink, and a clip. Fifteen studies evaluated one-step procedures, with the identification rate of the targeted lymph node at surgery varying from 8 of 13 to 47 of 47. Forty-one studies evaluated two-step procedures, with the identification rate of the clipped targeted lymph node on imaging after neoadjuvant systemic therapy varying from 49 to 100%, and the identification rate of the targeted lymph node at surgery from 17 of 24 to 100%. Most studies (40 of 51) were rated as being of fair quality. CONCLUSION: Various targeted axillary dissection procedures are used in clinical practice. Owing to study heterogeneity, the optimal targeted lymph node excision technique in terms of identification rate and feasibility could not be determined. Two-step procedures are at risk of not identifying the clipped targeted lymph node on imaging after neoadjuvant systemic therapy.

Real-world data on malignant and borderline phyllodes tumors of the breast: A population-based study of all 921 cases in the Netherlands (1989 -2020).

AIM: The aim of our study is to analyze patterns in treatment and outcome in a population-based series of patients with borderline and malignant phyllodes tumors (PT). MATERIAL AND METHODS: Data on all patients with a borderline or malignant PT (1989-2020) were extracted from the Netherlands Cancer Registry and the Dutch nationwide pathology databank (Palga) and retrospectively analyzed. RESULTS: We included 921 patients (borderline PT n = 452 and malignant PT n = 469). Borderline PT patients more often had breast-conserving surgery (BCS) as final surgery (81 vs. 46%). BCS rates for borderline PT increased over time (OR 1.08 per year, 95%CI 1.04 - 1.13, P < 0.001). In malignant PT adjuvant radiotherapy was given in 14.7%; this rate increased over time (OR 1.07 per year, 95%CI 1.02 - 1.13, P = 0.012). Local recurrence rate (5-year estimate of cumulative incidence) was 8.7% (95%CI 6.0-11.4) for borderline PT and 11.7% (95%CI 8.6-14.8) for malignant PT (P = 0.187) and was related to tumor size ≥ 20 mm (HR 10.6 (95%CI 1.5-76.8) and positive margin (HR 3.0 (95%CI 1.6-5.6), p < 0.001), but not to negative margin width (HR 1.3 ( 95%CI 0.7-2.3), p = 0.350)). Distant metastasis occurred only in malignant PT with a 5-year cumulative incidence of 4.7% (95%CI 3.3 - 6.1). CONCLUSION: This population-based series showed an increase in BCS in borderline PT and an increase in adjuvant radiotherapy in malignant PT over time. We identified malignant PT, BCS, larger tumor size and positive final margins as possible risk factors for local recurrence. Small but negative margins can be accepted.

EUSOMA quality indicators for non-metastatic breast cancer: An update.

INTRODUCTION: Quality care in breast cancer is higher if patients are treated in a Breast Center with a dedicated and specialized multidisciplinary team. Quality control is an essential activity to ensure quality care, which has to be based on the monitoring of specific quality indicators. Eusoma has proceeded with the up-dating of the 2017 Quality indicators for non-metastatic breast cancer based on the new diagnostic, locoregional and systemic treatment modalities. METHODS: To proceed with the updating, EUSOMA setup a multidisciplinary working group of BC experts and patients' representatives. It is a comprehensive set of QIs for early breast cancer care, which are classified as mandatory, recommended, or observational. For the first time patient reported outcomes (PROMs) have been included. As used in the 2017 EUSOMA QIs, evidence levels were based on the short version of the US Agency for Healthcare Research and Quality. RESULTS: This is a set of quality indicators representative for the different steps of the patient pathway in non-metastatic setting, which allow Breast Centres to monitor their performance with referring standards, i.e minimum standard and target. CONCLUSIONS: Monitoring these Quality Indicators, within the Eusoma datacentre will allow to have a state of the art picture at European Breast Centres level and the development of challenging research projects.

Breast surgery after neoadjuvant chemotherapy in patients with lobular carcinoma: surgical and oncologic outcome.

INTRODUCTION: Breast cancer patients with invasive lobular carcinoma (ILC) have an increased risk of positive margins after surgery and often show little response to neoadjuvant chemotherapy (NAC). We aimed to investigate surgical outcomes in patients with ILC treated with NAC. METHODS: In this retrospective cohort study, all breast cancer patients with ILC treated with NAC who underwent surgery at the Netherlands Cancer Institute from 2010 to 2019 were selected. Patients with mixed type ILC in pre-NAC biopsies were excluded if the lobular component was not confirmed in the surgical specimen. Main outcomes were tumor-positive margins and re-excision rate. Associations between baseline characteristics and tumor-positive margins were assessed, as were complications, locoregional recurrence rate (LRR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: We included 191 patients. After NAC, 107 (56%) patients had breast conserving surgery (BCS) and 84 (44%) patients underwent mastectomy. Tumor-positive margins were observed in 67 (35%) patients. Fifty five (51%) had BCS and 12 (14%) underwent mastectomy (p value < 0.001). Re-excision was performed in 35 (33%) patients with BCS and in 4 (5%) patients with mastectomy. Definitive surgery was mastectomy in 107 (56%) patients and BCS in 84 (44%) patients. Tumor-positive margins were associated with cT ≥ 3 status (OR 4.62, 95% CI 1.26-16.98, p value 0.021) in the BCS group. Five-year LRR (4.7%), RFS (81%), and OS (93%) were not affected by type of surgery after NAC. CONCLUSION: Although 33% of ILC breast cancer patients undergoing BCS after NAC required re-excision for positive resection margins, it is considered safe given that five-year RFS remained excellent and LRR and OS did not differ by extent of surgery.

Comparative Effectiveness of Psychotherapy vs Antidepressants for Depression in Heart Failure: A Randomized Clinical Trial.

Importance: Heart failure (HF) affects more than 6 million adults in the US and more than 64 million adults worldwide, with 50% prevalence of depression. Patients and clinicians lack information on which interventions are more effective for depression in HF. Objective: To compare the effectiveness of behavioral activation psychotherapy (BA) vs antidepressant medication management (MEDS) on patient-centered outcomes inpatients with HF and depression. Design, Setting, and Participants: This pragmatic randomized comparative effectiveness trial was conducted from 2018 to 2022, including 1-year follow-up, at a not-for-profit academic health system serving more than 2 million people from diverse demographic, socioeconomic, cultural, and geographic backgrounds. Participant included inpatients and outpatients diagnosed with HF and depression, and data were analyzed as intention-to-treat. Data were analyzed from 2022 to 2023. Interventions: BA is an evidence-based manualized treatment for depression, promoting engagement in personalized pleasurable activities selected by patients. MEDS involves the use of an evidence-based collaborative care model with care managers providing coordination with patients, psychiatrists, and primary care physicians to only administer medications. Main Outcomes and Measures: The primary outcome was depressive symptom severity at 6 months, measured using the Patient Health Questionnaire 9-Item (PHQ-9). Secondary outcomes included physical and mental health-related quality of life (HRQOL), measured using the Short-Form 12-Item version 2 (SF-12); heart failure-specific HRQOL, measured using the Kansas City Cardiomyopathy Questionnaire; caregiver burden, measured with the Caregiver Burden Questionnaire for Heart Failure; emergency department visits; readmissions; days hospitalized; and mortality at 3, 6, and 12 months. Results: A total of 416 patients (mean [SD] age, 60.71 [15.61] years; 243 [58.41%] male) were enrolled, with 208 patients randomized to BA and 208 patients randomized to MEDS. At baseline, mean (SD) PHQ-9 scores were 14.54 (3.45) in the BA group and 14.31 (3.60) in the MEDS group; both BA and MEDS recipients experienced nearly 50% reduction in depressive symptoms at 3, 6, and 12 months (eg, mean [SD] score at 12 months: BA, 7.62 (5.73); P < .001; MEDS, 7.98 (6.06); P < .001; between-group P = .55). There was no statistically significant difference between BA and MEDS in the primary outcome of PHQ-9 at 6 months (mean [SD] score, 7.53 [5.74] vs 8.09 [6.06]; P = .88). BA recipients, compared with MEDS recipients, experienced small improvement in physical HRQOL at 6 months (mean [SD] SF-12 physical score: 38.82 [11.09] vs 37.12 [10.99]; P = .04), had fewer ED visits (3 months: 38% [95% CI, 14%-55%] reduction; P = .005; 6 months: 30% [95% CI, 14%-40%] reduction; P = .008; 12 months: 27% [95% CI, 15%-38%] reduction; P = .001), and spent fewer days hospitalized (3 months: 17% [95% CI, 8%-25%] reduction; P = .002; 6 months: 19% [95% CI, 13%-25%] reduction; P = .005; 12 months: 36% [95% CI, 32%-40%] reduction; P = .001). Conclusions and Relevance: In this comparative effectiveness trial of BA and MEDS in patients with HF experiencing depression, both treatments significantly reduced depressive symptoms by nearly 50% with no statistically significant differences between treatments. BA recipients experienced better physical HRQOL, fewer ED visits, and fewer days hospitalized. The study findings suggested that patients with HF could be given the choice between BA or MEDS to ameliorate depression. Trial Registration: ClinicalTrials.gov Identifier: NCT03688100.

Prognostic effect of nodal status before and after neoadjuvant chemotherapy in breast cancer: a Dutch population-based study.

PURPOSE: In breast cancer, neoadjuvant chemotherapy (NAC) can downstage the nodal status, and can even result in a pathological complete response, which is associated with improved prognosis. This study aimed to determine the prognostic effect of nodal status before and after NAC. METHODS: Women with breast cancer treated with NAC were selected from the Netherlands Cancer Registry if diagnosed between 2005 and 2019, and classified based on nodal status before NAC: node-negative (cN0), or node-positive based on fine needle aspiration cytology or core needle biopsy (cN+). Subgroups were based on nodal status after NAC: absence (ypN0) or presence (ypN+) of nodal disease. Five-year overall survival (OS) was assessed with Kaplan-Meier survival analyses, also per breast cancer molecular subtype. To adjust for potential confounders, multivariable analyses were performed. RESULTS: A total of 6,580 patients were included in the cN0 group, and 11,878 in the cN+ group. The 5-year OS of the cN0ypN0-subgroup was statistically significant better than that of the cN+ypN0-subgroup (94.4% versus 90.1%, p < 0.0001). In cN0 as well as cN+ disease, ypN+ had a statistically significant worse 5-year OS compared to ypN0. For hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)-, HR+ HER2+, HR-HER2+, and triple negative disease, respectively, 5-year OS in the cN0ypN+-subgroup was 89.7%, 90.4%, 73.7%, and 53.6%, and in the cN+ypN+-subgroup 84.7%, 83.2%, 61.4%, and 48.8%. In multivariable analyses, cN+ and ypN+ disease were both associated with worse OS. CONCLUSION: This study suggests that both cN-status and ypN-status, and molecular subtype should be considered to further improve prognostication.

Diffuse reflectance spectroscopy for accurate margin assessment in breast-conserving surgeries: importance of an optimal number of fibers.

During breast-conserving surgeries, it remains challenging to accomplish adequate surgical margins. We investigated different numbers of fibers for fiber-optic diffuse reflectance spectroscopy to differentiate tumorous breast tissue from healthy tissue ex vivo up to 2 mm from the margin. Using a machine-learning classification model, the optimal performance was obtained using at least three emitting fibers (Matthew's correlation coefficient (MCC) of 0.73), which was significantly higher compared to the performance of using a single-emitting fiber (MCC of 0.48). The percentage of correctly classified tumor locations varied from 75% to 100% depending on the tumor percentage, the tumor-margin distance and the number of fibers.

High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: the randomized phase III NeoTN trial.

Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23-1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03-0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30-3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24-87%), 71% (95% CI 48-100%) and 88% (95% CI 74-100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069.

Alzheimer risk-increasing TREM2 variant causes aberrant cortical synapse density and promotes network hyperexcitability in mouse models.

The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimer's disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-ß sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.