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Background: Radiation associated angiosarcoma (RAAS) of the breast is a rare malignancy with poor survival. Optimal treatment strategies remain uncertain due to a lack of data, and vary between surgery alone and a combination of surgery with (neo)adjuvant chemotherapy (NACT) and/or re-irradiation. The aim of this study was to evaluate the potential benefit of taxane based NACT., Methods: In this retrospective single center study, all patients with RAAS of the breast treated between 1994 and 2024 are included. Since 2018, NACT is considered a treatment option for this patient population in our institute. The difference in oncological outcomes of patients with and without NACT were compared., Results: Thirty-five women were included. Thirteen (37 %) received NACT of which five (39 %) also had neoadjuvant re-irradiation with hyperthermia. Eleven patients (85 %) received paclitaxel, the other two (15 %) had doxorubicine/docetaxel. Complete pathological response was found in 69 % (n = 9). Median follow up was 41 months (range 24-56) for patients with NACT and 44 (range 20-108) for patients without NACT. In the NACT group, only one patient developed a recurrence after 6.5 years. Patients with NACT had improved oncological outcomes compared to patients without NACT in terms of 3-year local recurrence free survival (100% vs. 63.9 %, p = 0.14), distant metastasis free survival (100 % vs. 47.5 %, p = 0.005), and overall survival (100% vs. 56.1 %, p = 0.016)., Conclusion: In this study, neoadjuvant taxanes for RAAS of the breast leads to improved distant metastasis free survival and overal survival in patients treated with NACT compared to no NACT., Competing Interests: Declaration of competing interest N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte, Luszana. N Steeghs received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, Merck Sharp & DohmeMerck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute. W. van der Graaf: Advisory boards SpringworkTx, Agenus and PTC Therapeutics (all to the institute) and research grants from Eli Lilly (to the Institute). W. van Houdt: advisory boards of Amgen, Boehringer Ingelheim, Sanofi, Novartis, Sirius Pintuition, Belpharma. All payment to the Netherlands Cancer Institute., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: Disclosures: Eva Heeling, Gaelle M. Kramer, José H. Volders, and Marie-Jeanne T.F.D. Vrancken Peeters have no conflicts of interest to declare that may be relevant to the contents of this 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, the authors investigated the effect of breast reconstruction with macro-textured SBIs on long-term oncologic outcomes of breast cancer patients., Materials and Methods: The authors conducted a retrospective cohort study in two large cancer centres in the Netherlands. Patients who had been treated for primary breast cancer between 1 January 2000 and 31 December 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 were accounted for by multiple imputations 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 4695 women who were eligible for inclusion, 2393 had undergone mastectomy. Of these women, 1187 (25%) had received breast reconstruction with a macro-textured SBI. The 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 various 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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: An increasing number of breast cancer patients undergo breast-conserving surgery (BCS), but multiple ipsilateral breast cancer (MIBC) is still considered a relative contraindication for breast conservation. This study provides an update on trends in the surgical management for MIBC over a 10-year period., Methods: Nationwide data from the Netherlands Cancer Registration of all patients diagnosed with breast cancer between 2011 and 2021 were analysed. The primary outcomes of this study were the incidence of MIBC and the trend in breast surgery type among patients between 2011 and 2021. Secondary outcomes were the positive resection margin rates in patients treated with BCS, the proportion of patients requiring re-excision and overall survival., Results: In total, 114 433 patients (83%) with unifocal breast cancer and 23 932 patients (17%) with MIBC were identified. The incidence of MIBC was stable (17%) over the years. Overall BCS rates, both primary and after neoadjuvant chemotherapy, increased in MIBC from 29% in 2011 to 41% in 2021. Re-excision was performed in 1348 patients (n = 8455, 16%). The 5-year OS estimate for patients with MIBC treated with BCS was 93%. The pathological complete response (pCR) in MIBC patients treated with neoadjuvant chemotherapy followed by mastectomy was 23%., Conclusion: The breast conservation rate in MIBC has increased over the last decade. In addition, 23% of MIBC patients treated with neoadjuvant chemotherapy followed by mastectomy achieved a pCR. This suggests increasing opportunities for even more BCS in MIBC., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: F.E. van Leeuwen reports financial support was provided by Netherlands Ministry of Health Welfare and Sport. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J.P.O., C.F.J., S.A.L.B., C.E.L., J.S., M.T.F.D.V., C.A.D., F.H.D. declare no competing financial or non-financial interests. M.K. reports research funding paid to the institute from BMS, Roche and AstraZeneca and an advisory for AstraZeneca, Daiichi Sankyo, Domain Therapeutics, Alderaan, BMS, MSD and Roche., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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/m 2 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., Competing Interests: Declaration of interests GSS reports receiving institutional research funding from Agendia, AstraZeneca, Merck, Novartis, Roche, and Seagen; and consulting fees from Biovica and Seagen. RMM reports receiving institutional research funding from Siemens Healthineers, Bayer Healthcare, Beckton & Dickinson, Screenpoint Medical, Koning, Lunit, PA Imaging, the Dutch Research Council, European Research Council, Dutch Cancer Society, European Union, and EFRO/OP-Oost; consulting fees from Siemens Healthineers, Bayer Healthcare, Beckton & Dickinson, Guerbet, Bracco, and Screenpoint Medical; is an advisory editorial board member of European Radiology; is an associate editor for breast imaging of the Radiology journal; is a member of the scientific committee of European Society of Radiology and Dutch Breast Cancer Research Group (chair working group for diagnostics); and is a member of the executive board of the European Society of Breast Imaging. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© 2024 The Authors.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Phyllodes tumors (PTs) are rare tumors of the breast. The current National Comprehensive Cancer Network (NCCN) guidelines recommend excision of benign PTs, accepting close or positive margins. Controversy about the optimal treatment for benign PTs remains, especially regarding the preferred margin width after surgical excision and the need for follow-up evaluation., Methods: A nationwide retrospective study analyzed the Dutch population from 1989 to 2022. All patients with a diagnosis of benign PT were identified through a search in the Dutch nationwide pathology databank (Palga). Information on age, year of diagnosis, size of the primary tumor, surgical treatment, surgical margin status, and local recurrence was collected., Results: The study enrolled 1908 patients with benign PT. The median age at diagnosis was 43 years (interquartile range [IQR], 34-52 years), and the median tumor size was 30 mm (IQR, 19-40 mm). Most of the patients (95%) were treated with breast-conserving surgery (BCS). The overall local recurrence rate was 6.2%, and the median time to local recurrence was 31 months (IQR, 15-61 months). Local recurrence was associated with bilaterality of the tumor (odds ratio [OR], 4.91; 95% confidence interval [CI], 2.95-28.30) and positive margin status (OR, 2.51; 95% CI 1.36-4.63). The local recurrence rate was 8.9% for the patients with positive excision margins and 4.0% for the patients with negative excision margins. Notably, for 27 patients (22.6%) who experienced a local recurrence, histologic upgrading of the recurrent tumor was reported, 7 (5.9%) of whom had recurrence as malignant lesions., Conclusions: This nationwide series of 1908 patients showed a low local recurrence rate of 6.2% for benign PT, with higher recurrence rates following positive margins., (© 2023. Society of Surgical Oncology.)

The increasing use and effectiveness of primary systemic treatment (PST) enables tailored locoregional treatment. About one third of clinically node positive (cN+) breast cancer patients achieve pathologic complete response (pCR) of the axilla, with higher rates observed in Human Epidermal growth factor Receptor (HER)2-positive or triple negative (TN) breast cancer subtypes. Tailoring axillary treatment for patients with axillary pCR is necessary, as they are unlikely to benefit from axillary lymph node dissection (ALND), but may suffer complications and long-term morbidity such as lymphedema and impaired shoulder motion. By combining pre-PST and post-PST axillary staging techniques, ALND can be omitted in most cN + patients with pCR. Different post-PST staging techniques (MARI/TAD/SN) show low or ultra-low false negative rates for detection of residual disease. More importantly, trials using the MARI (Marking Axillary lymph nodes with Radioactive Iodine seeds) procedure or sentinel lymph node biopsy (SLNB) as axillary staging technique post-PST have already shown the safety of tailoring axillary treatment in patients with an excellent response. Tailored axillary treatment using the MARI procedure in stage I-III breast cancer resulted in 80% reduction of ALND and excellent five-year axillary recurrence free interval (aRFI) of 97%. Similar oncologic outcomes were seen for post-SLNB in stage I-II patients. The MARI technique requires only one invasive procedure pre-NST and a median of one node is removed post-PST, whereas for the SLNB and TAD techniques two to four nodes are removed. A disadvantage of the MARI technique is its use of radioactive iodine, which is subject to extensive regulations., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast conserving surgery (BCS) plus radiation treatment is the favored alternative for mastectomy in patients with breast cancer. To allow for breast conservation in patients with large invasive tumors and poor response to neoadjuvant systemic treatment (NST) or patients with extensive ductal carcinoma in situ (DCIS), oncoplastic breast conserving surgery (OPBCS) techniques are introduced. OPBCS allows for breast conservation in a selective group of breast cancer patients who initially would have been treated with mastectomy due to the unfavorable tumor-to-breast ratio. With OPBCS, the oncological tumor excision is combined with plastic surgical breast conservation techniques without compromising oncological safety and maintaining aesthetic outcomes by preserving the shape of the breast. OPBCS should however not be applied to all breast cancer patients and the selection of patients who benefit from OPBCS and the timing of OPBCS are best discussed in a multidisciplinary team (MDT). Caution is required in patients with higher risk of positive margins [e.g., multifocal breast cancer, invasive lobular carcinoma (ILC), larger tumors and DCIS]. In these patients, delayed OPBCS is recommended to facilitate re-excision and maintain excellent breast conserving rates. Despite proven benefits in selected patients, the increase in the adoption of OPBCS is relatively low. This article provides a clinical perspective on OPBCS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-23-40/coif). The authors have no conflicts of interest to declare., (2023 Translational Breast Cancer Research. All rights reserved.)

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., (© 2023. Springer Nature Limited.)

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., Competing Interests: The authors declare no conflicts of interest., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Introduction: Some aspects of the treatment protocol for breast cancer during pregnancy (PrBC) have not been thoroughly studied. This study provides clarity regarding the safety of the use of 125 I-seeds as a localization technique for breast-conserving surgery in patients with PrBC., Methods: To calculate the exposure to the fetus of one 125 I-seed implanted in a breast tumor, we developed a model accounting for the decaying 125 I-source, time to surgery, and the declining distance between the 125 I-seed and the fetus. The primary outcome was the maximum cumulative fetal dose of radiation at consecutive gestational ages (GA)., Results: The cumulative fetal dose remains below 1 mSv if a single 125 I-seed is implanted at a GA of 26 weeks. After a GA of 26 weeks, the fetal dose can be at a maximum of 11.6 mSv. If surgery takes place within two weeks of implantation from a GA of 26 weeks, and one week above a GA of 32 weeks, the dose remains below 1 mSv., Conclusion: The use of 125 I-seeds is safe in PrBC. The maximum fetal exposure remains well below the threshold of 100 mSv, and therefore, does not lead to an increased risk of fetal tissue damage. Still, we propose keeping the fetal dose as low as possible, preferably below 1 mSv.

Background: Implant-based breast reconstructions contribute considerably to the quality of life of breast cancer patients. A knowledge gap exists concerning the potential role of silicone breast implants in the development of so-called "breast implant illness" (BII) and autoimmune diseases in breast cancer survivors with implant-based reconstructions. BII is a constellation of non-specific symptoms reported by a small group of women with silicone breast implants., Methods: The Areola study is a multicenter retrospective cohort study with prospective follow-up aiming to assess the risk of BII and autoimmune diseases in female breast cancer survivors with and without silicone breast implants. In this report, we set out the rationale, study design, and methodology of this cohort study. The cohort consists of breast cancer survivors who received surgical treatment with implant-based reconstruction in six major hospitals across the Netherlands in the period between 2000 and 2015. As a comparison group, a frequency-matched sample of breast cancer survivors without breast implants will be selected. An additional group of women who received breast augmentation surgery in the same years will be selected to compare their characteristics and health outcomes with those of breast cancer patients with implants. All women who are still alive will be invited to complete a web-based questionnaire covering health-related topics. The entire cohort including deceased women will be linked to population-based databases of Statistics Netherlands. These include a registry of hospital diagnostic codes, a medicines prescription registry, and a cause-of-death registry, through which diagnoses of autoimmune diseases will be identified. Outcomes of interest are the prevalence and incidence of BII and autoimmune diseases. In addition, risk factors for the development of BII and autoimmune disorders will be assessed among women with implants., Discussion: The Areola study will contribute to the availability of reliable information on the risks of BII and autoimmune diseases in Dutch breast cancer survivors with silicone breast implants. This will inform breast cancer survivors and aid future breast cancer patients and their treating physicians to make informed decisions about reconstructive strategies after mastectomy., Registration: This study is registered at ClinicalTrials.gov on June 2, 2022 (NCT05400954)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The NABON Breast Cancer Audit showed that more than 70% of the Dutch women undergoing surgery for breast cancer maintained their breast contour by breast-conserving surgery (BCS) or by immediate reconstruction after ablative surgery. The proportion of oncoplastic surgery applied in patients undergoing breast-conserving treatment remains unknown. The aim of our study was to assess the need for standardization of oncoplastic breast-conserving surgery (OPBCS) in an attempt to enable measurement of the quality of OPBCS., Methods: To gain a better understanding of current practice in OPBCS, we sent a questionnaire to all breast surgeons in The Netherlands who are members of the breast surgery working group ( n = 134)., Results: A total of 60 breast surgeons, representing different hospitals in The Netherlands, responded. 61.7% of the breast surgeons performed BCS on 60-100% of their patients. 68.3% responded that BCS was performed using OPS techniques in up to 40% of their patients. OPBCS was defined as level I volume displacement by 45.2% of the breast surgeons and as BCS performed by a breast surgeon and plastic surgeon together by 32.3% of the breast surgeons. 94.5% indicated that there is a need for standardization of the definition of OPBCS in The Netherlands., Conclusion: This study demonstrates that OPBCS is a major part of daily clinical practice of Dutch breast surgeons treating BC patients. Despite this, there is no clear definition of OPS in breast-conserving treatment in The Netherlands. Only after standardization can a classification code and quality indicator be initiated for OPBCS. Ultimately, this will facilitate improvement in quality of BC care., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Purpose: Neoadjuvant systemic therapy (NST) is increasingly used in breast cancer patients and depending on subtype, 10-89% of patients will attain pathologic complete response (pCR). In patients with pCR, risk of local recurrence (LR) after breast conserving therapy is low. Although adjuvant radiotherapy after breast conserving surgery (BCS) reduces LR further in these patients, it may not contribute to overall survival. However, radiotherapy may cause early and late toxicity. The aim of this study is to show that omission of adjuvant radiotherapy in patients with a pCR after NST will result in acceptable low LR rates and good quality of life., Methods: The DESCARTES study is a prospective, multicenter, single arm study. Radiotherapy will be omitted in cT1-2N0 patients (all subtypes) who achieve a pCR of the breast and lymph nodes after NST followed by BCS plus sentinel node procedure. A pCR is defined as ypT0N0 (i.e. no residual tumor cells detected). Primary endpoint is the 5-year LR rate, which is expected to be 4% and deemed acceptable if less than 6%. In total, 595 patients are needed to achieve a power of 80% (one-side alpha of 0.05). Secondary outcomes include quality of life, Cancer Worry Scale, disease specific and overall survival. Projected accrual is five years., Conclusion: This study bridges the knowledge gap regarding LR rates when adjuvant radiotherapy is omitted in cT1-2N0 patients achieving pCR after NST. If the results are positive, radiotherapy may be safely omitted in selected breast cancer patients with a pCR after NST., Trial Registration: This study is registered at ClinicalTrials.gov on June 13th 2022 (NCT05416164). Protocol version 5.1 (15-03-2022)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In immediate implant-based breast reconstruction (IBBR), large variation is observed in current practices between a direct-to-implant and a two-stage approach (insertion of a breast implant after a tissue expander). This population-based study aimed to compare unplanned short- and long-term revision incidence between direct-to-implant and two-stage IBBR in The Netherlands., Methods: All patients who underwent immediate IBBR following a mastectomy between 2015 and 2019 were selected from the nationwide Dutch Breast Implant Registry. Short- and long-term unplanned revision incidences were studied per immediate IBBR, including revision indications and the total number of additional operations. Confounding by indication was limited using propensity score matching., Results: A total of 4512 breast implants (3948 women) were included, of which 2100 (47%) were for direct-to-implant IBBR and 2412 (53%) were for two-stage IBBR. Median (IQR) follow-up was 29 months (range, 16 to 45 months) and 33 months (range, 21 to 47 months), respectively. Short-term revision incidence was 4.0% and 11.7%, respectively (conditional OR, 0.31; 95% CI, 0.23 to 0.42%). Long-term revision incidence was 10.6% (95% CI, 9.2 to 12.1%) and 16.4% (95% CI, 14.8 to 17.9%), respectively. In the propensity score-matched cohort, similar results were found. In the direct-to-implant group, more breasts were reconstructed within the planned number of operations than in the two-stage group., Conclusions: Unplanned revision surgery occurred less often after direct-to-implant IBBR, and more breasts were reconstructed within the planned number of operations compared to two-stage IBBR. These results, based on real-world data, are important for improving patient counseling and shared decision-making., Clinical Question/level of Evidence: Risk, II., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Purpose: Oncoplastic surgery (OPS) after breast conserving surgery is preferably performed during the same operation. Offering delayed OPS instead of mastectomy to patients with a high risk of tumor-positive margins allows breast conservation with the option of margin re-excision during OPS, without having to dismantle the reconstruction. We aimed to evaluate surgical outcomes after immediate and delayed OPS., Methods: We included early-stage breast cancer patients who underwent OPS at the Netherlands Cancer Institute between 2016 and 2019. Patients were selected for delayed OPS after multidisciplinary consultation if the risk of tumor-positive margins with immediate OPS was considered significant (> 30%). Groups were compared on baseline characteristics and short-term surgical outcomes., Results: Of 242 patients with 251 OPS, 130 (52%) OPS had neoadjuvant chemotherapy. Immediate OPS was performed in 176 (70%) cases and delayed OPS in 76 (30%). Selection for delayed OPS was associated with tumor size (OR 1.03, 95% CI 1.01-1.04), ILC (OR 2.61, 95% CI 1.10-6.20), DCIS (OR 3.45, 95% CI 1.42-8.34) and bra size (OR 0.76, 95% CI 0.62-0.94). Delayed and immediate OPS differed in tissue weight (54 vs. 67 g, p = 0.034), tissue replacement (51% vs. 26%, p < .001) and tumor-positive margins (66% vs. 18%, p < .001). Re-excision was performed in 48 (63%) delayed OPS and in 11 (6%) immediate OPS. Groups did not differ in complications (21% vs. 18%, p = 0.333). Breast conservation after immediate and delayed OPS was 98% and 93%, respectively., Conclusion: Performing delayed OPS in selected cases facilitated simultaneous margin re-excision without increasing complications, and resulted in an excellent breast conservation rate., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

There is an unmet clinical need for an accurate, rapid and reliable tool for margin assessment during breast-conserving surgeries. Ultrasound offers the potential for a rapid, reproducible, and non-invasive method to assess margins. However, it is challenged by certain drawbacks, including a low signal-to-noise ratio, artifacts, and the need for experience with the acquirement and interpretation of images. A possible solution might be computer-aided ultrasound evaluation. In this study, we have developed new ensemble approaches for automated breast tumor segmentation. The ensemble approaches to predict positive and close margins (distance from tumor to margin ≤ 2.0 mm) in the ultrasound images were based on 8 pre-trained deep neural networks. The best optimum ensemble approach for segmentation attained a median Dice score of 0.88 on our data set. Furthermore, utilizing the segmentation results we were able to achieve a sensitivity of 96% and a specificity of 76% for predicting a close margin when compared to histology results. The promising results demonstrate the capability of AI-based ultrasound imaging as an intraoperative surgical margin assessment tool during breast-conserving surgery.

Background: In breast cancer patients treated with neoadjuvant systemic therapy (NST), MRI is used pre- and post-NST for response monitoring. The relevance of additional MRI-detected lesions in these patients is unclear. Therefore, we aimed to assess the impact of pre-NST MRI-detected additional lesions on surgical treatment and outcome., Methods: We retrospectively selected all early-stage breast cancer patients with MRI pre-NST at our institute from January 2010-2015. MRI-detected lesions were defined as separated from the index tumor and occult at conventional mammography and ultrasound. Outcomes were change in surgical treatment and five-year recurrence-free and overall survival., Results: Overall, MRI detected additional lesions in 206 (31%) of 656 patients: in 160 patients in the ipsilateral breast and in 78 contralateral breasts, including 32 bilateral cases. Ipsilateral lesions were mostly categorized BI-RADS 5 (54 %) and contralateral lesions BI-RADS 3 (64%). Targeted ultrasound was performed in 115 (56%) patients: in 70 ipsilateral and in 64 contralateral cases. Biopsy was obtained in 44 (28% of 160) ipsilateral and 50 (64% of 78) contralateral breasts, containing tumor foci in 20 (13% of 160) and 11 (14% of 78) cases, respectively. Surgical treatment changed in 54 (26% of 206) patients: 19 (9%) had mastectomy, 24 (12%) had wider local excision and 11 (5%) underwent contralateral surgery. Five-year recurrence-free and overall survival did not differ for patients with local excision or mastectomy., Conclusion: Pre-NST MRI-detected additional lesions in 31% of patients, resulting in more extensive surgery in 26% of these patients, including 5% contralateral surgeries., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: We aimed to compare (1) treatments and time intervals between treatments of breast cancer patients diagnosed during and before the COVID-19 pandemic, and (2) the number of treatments started during and before the pandemic., Methods: Women were selected from the Netherlands Cancer Registry. For aim one, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the treatment of women diagnosed within four periods of 2020: pre-COVID (weeks 1-8), transition (weeks 9-12), lockdown (weeks 13-17), and care restart (weeks 18-26), with data from 2018/2019 as reference. Wilcoxon rank-sums test was used to compare treatment intervals, using a two-sided p-value < 0.05. For aim two, number of treatments started per week in 2020 was compared with 2018/2019., Results: We selected 34,097 women for aim one. Compared to 2018/2019, neo-adjuvant chemotherapy was less likely for stage I (OR 0.24, 95%CI 0.11-0.53), stage II (OR 0.63, 95%CI 0.47-0.86), and hormone receptor+/HER2- tumors (OR 0.55, 95%CI 0.41-0.75) diagnosed during transition. Time between diagnosis and first treatment decreased for patients diagnosed during lockdown with a stage I (p < 0.01), II (p < 0.01) or III tumor (p = 0.01). We selected 30,002 women for aim two. The number of neo-adjuvant endocrine therapies and surgeries starting in week 14, 2020, increased by 339% and 18%, respectively. The number of adjuvant chemotherapies decreased by 42% in week 15 and increased by 44% in week 22., Conclusion: The pandemic and subsequently altered treatment recommendations affected multiple aspects of the breast cancer treatment strategy and the number of treatments started per week., (© 2022. The Author(s).)

Breast cancer is the most commonly occurring malignancy in women. Every year, this type of cancer is newly diagnosed in almost 15,000 women and over 100 men in the Netherlands. Survival depends on the stage of disease and has improved over time. However, every year approximately 3100 women die of breast cancer in the Netherlands. Recent developments in breast cancer care focus on more breast and axilla conserving treatments, and the omission or more limited application of adjuvant chemotherapy or additional radiotherapy if it is deemed safe. In this educational article we discuss aspects of detection, diagnosis, treatment and follow-up of breast cancer.

Purpose: Repeat sentinel lymph node biopsy (rSLNB) has been suggested for axillary staging in clinically node-negative (cN0) patients with ipsilateral breast tumor recurrence (IBTR). Although rSLNB is technically feasible in this group of patients, the clinical value has not been established. We aimed to assess the added value of rSLNB in cN0 patients with IBTR who underwent optimal clinical staging with FDG-PET/CT., Methods: This retrospective single-center cohort study included 119 patients with IBTR-staged cT1-4N0M0 with FDG-PET/CT who underwent rSLNB between 2006 and 2020. Overall recurrence-free survival (RFS) and overall survival (OS) were calculated for subgroups with tumor-positive, tumor negative, and unsuccessful rSLNB., Results: rSLNB was successful in 79 (66%) of the 119 included patients, of whom 70 (59%) had a tumor negative and 9 (8%) a tumor-positive rSLNB; rSLNB was unsuccessful in the remaining 40 (34%) patients. Patients with a tumor-positive rSLNB had poorer overall 5-year RFS compared to patients with a tumor negative or unsuccessful rSLNB (44% vs. 86% vs. 90%, p = 0.004). Although patients with a tumor-positive rSLNB had worse RFS, the 10-year OS was comparable to a tumor negative or unsuccessful rSLNB (89% vs. 89% vs. 95%, p = 0.701)., Conclusion: The incidence of a tumor-positive rSLNB in patients with a negative FDG-PET/CT is low and does not change survival. Therefore, in cN0 patients with IBTR who underwent optimal clinical staging with FDG-PET/CT, we support a patient- and tumor-tailored treatment strategy in which rSLNB may be omitted., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background  Postmastectomy radiotherapy (PMRT) is allegedly associated with a higher risk of complications of combined nipple-sparing or skin-sparing mastectomy and subpectoral direct-to-implant immediate breast reconstruction ([N]SSM/SDTI-IBR). For this reason, this combination is usually advised against or, even, refused in women who need to undergo PMRT. Because this advice has never been justified, we assessed the short-term complications that may potentially be associated with PMRT after [N]SSM/SDTI-IBR. Methods  We compared the complications requiring reintervention and implant loss occurring after 273 [N]SSM/SDTI-IBR that were exposed to PMRT within the first 16 postoperative weeks (interventional group) to those occurring in 739 similarly operated breasts that were not (control group). Additionally, we compared the fraction of complications requiring reintervention occurring after the onset of radiotherapy in the interventional group to that occurring after a comparable postoperative period in the control group. Results  The fraction of breasts requiring unscheduled surgical reinterventions for complications and the loss of implants did not differ significantly between both groups but significantly more reinterventions were needed among the controls ( p  = 0.00). The fraction of events after the onset of radiotherapy in the interventional group was higher than the fraction of events after 6.2 weeks in the control group, but not significantly so. Conclusion  We found no prove for the alleged increase of short-term complications of adjuvant radiotherapy. Therefore, we advise that these should not be considered valid arguments to advice against [N]SSM/SDTI-IBR., Competing Interests: Conflict of Interest None declared., (The Korean Society of Plastic and Reconstructive Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Purpose: In clinically node-positive (cN+) breast cancer patients, evidence supporting response-guided treatment after neoadjuvant systemic therapy (NST) instead of axillary lymph node dissection (ALND) is increasing, but follow-up results are lacking. We assessed three-year axillary recurrence-free interval (aRFI) in cN+ patients with response-adjusted axillary treatment according to the 'Marking Axillary lymph nodes with Radioactive Iodine seeds' (MARI)-protocol., Methods: We retrospectively assessed all stage II-III cytologically proven cN+ breast cancer patients who underwent the MARI-protocol between July 2014 and November 2018. Pre-NST axillary staging with FDG-PET/CT (less- or more than four suspicious axillary nodes; cALN < 4 or cALN ≥ 4) and post-NST pathological axillary response measured in the pre-NST largest tumor-positive axillary lymph node marked with an iodine seed (MARI-node; ypMARI-neg or ypMARI-pos) determined axillary treatment: no further treatment (cALN < 4, ypMARI-neg), axillary radiotherapy (ART) (cALN < 4, ypMARI-pos and cALN ≥ 4, ypMARI-neg) or ALND plus ART (cALN ≥ 4, ypMARI-pos)., Results: Of 272 women included, the MARI-node was tumor-negative in 56 (32%) of 174 cALN < 4 patients and 43 (44%) of 98 cALN ≥ 4 patients. According to protocol, 56 (21%) patients received no further axillary treatment, 161 (59%) received ART and 55 (20%) received ALND plus ART. Median follow-up was 3.0 years (IQR 1.9-4.1). Five patients (one no further treatment, four ART) had axillary metastases. Three-year aRFI was 98% (95% CI 96-100). The overall recurrence risk remained highest for patients with ALND (HR 4.36; 95% CI 0.95-20.04, p = 0.059)., Conclusions: De-escalation of axillary treatment according to the MARI-protocol prevented ALND in 80% of cN+ patients with an excellent three-year aRFI of 98%., (© 2022. The Author(s).)

Background: Radiotherapy (RT) is part of the curative treatment of approximately 70% of breast cancer (BC) patients. Wide practice variation has been reported in RT dose, fractionation and its treatment planning for BC. To decrease this practice variation, it is essential to first gain insight into the current variation in RT treatment between institutes. This paper describes the development of the NABON Breast Cancer Audit-Radiotherapy (NBCA-R), a structural nationwide registry of BC RT data of all BC patients treated with at least surgery and RT., Methods: A working group consisting of representatives of the BC Platform of the Dutch Radiotherapy Society selected a set of dose volume parameters deemed to be surrogate outcome parameters, both for tumour control and toxicity. Two pilot studies were carried out in six RT institutes. In the first pilot study, data were manually entered into a secured web-based system. In the second pilot study, an automatic Digital Imaging and Communications in Medicine (DICOM) RT upload module was created and tested., Results: The NBCA-R dataset was created by selecting RT parameters describing given dose, target volumes, coverage and homogeneity, and dose to organs at risk (OAR). Entering the data was made mandatory for all Dutch RT departments. In the first pilot study (N = 1093), quite some variation was already detected. Application of partial breast irradiation varied from 0 to 17% between the 6 institutes and boost to the tumour bed from 26.5 to 70.2%. For patients treated to the left breast or chest wall only, the average mean heart dose (MHD) varied from 0.80 to 1.82 Gy; for patients treated to the breast/chest wall only, the average mean lung dose (MLD) varied from 2.06 to 3.3 Gy. In the second pilot study 6 departments implemented the DICOM-RT upload module in daily practice. Anonymised data will be available for researchers via a FAIR (Findable, Accessible, Interoperable, Reusable) framework., Conclusions: We have developed a set of RT parameters and implemented registration for all Dutch BC patients. With the use of an automated upload module registration burden will be minimized. Based on the data in the NBCA-R analyses of the practice variation will be done, with the ultimate aim to improve quality of BC RT. Trial registration Retrospectively registered., (© 2022. The Author(s).)

Achieving an adequate resection margin during breast-conserving surgery remains challenging due to the lack of intraoperative feedback. Here, we evaluated the use of hyperspectral imaging to discriminate healthy tissue from tumor tissue in lumpectomy specimens. We first used a dataset obtained on tissue slices to develop and evaluate three convolutional neural networks. Second, we fine-tuned the networks with lumpectomy data to predict the tissue percentages of the lumpectomy resection surface. A MCC of 0.92 was achieved on the tissue slices and an RMSE of 9% on the lumpectomy resection surface. This shows the potential of hyperspectral imaging to classify the resection margins of lumpectomy specimens., Competing Interests: The authors declare no conflicts of interest., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Background: Node positive breast cancer (cN+) patients with an axillary pathologic complete response after neoadjuvant systemic therapy (NST) are not expected to benefit from axillary lymph node dissection (ALND). Therefore, less invasive axillary staging procedures have been introduced to establish response-guided treatment. However, evidence is lacking with regard to their oncologic safety and impact on quality of life (QoL). We hypothesize that if response-guided treatment is given, less invasive staging procedures are non-inferior to standard ALND in terms of oncologic safety, and superior to standard ALND in terms of QoL., Patients and Methods: MINIMAX is a Dutch multicenter registry study that includes patients with cN1-3M0 unilateral invasive breast cancer, who receive NST, followed by axillary staging and treatment according to local protocols. In a retrospective registry of ±4000 patients, the primary endpoint is oncologic safety at 5 and 10 years (disease-free, breast-cancer-specific and overall survival, and axillary recurrence rate). In a prospective multicenter registry, the primary endpoints are QoL at 1 and 5 years, and we aim to verify the 5-year oncologic safety. With an estimated 5-year disease-free survival of 72.5% and anticipated loss to follow-up of 10%, a sample size of 549 is needed to have 80% power to detect non-inferiority (with a 10% margin) of less invasive staging procedures., Conclusion: In cN+ patients treated with NST, less invasive axillary staging procedures are already implemented globally. Evidence is needed to support the assumed oncologic safety and superior QoL of such procedures. This study will contribute to evidence-based guidelines., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a trend towards de-escalating axillary staging and treatment in breast cancer patients. On account of neoadjuvant systemic therapy, node-positive breast cancer patients can achieve a pathological complete response of the axilla. It is hypothesized that these patients do not benefit from an axillary lymph node dissection (ALND), and thus may be spared the risk of severe post-surgical morbidity. In an effort to omit standard ALND, less invasive axillary staging procedures are being implemented to establish response-guided treatment. However, it is unclear which less invasive staging procedure is most accurate, and long-term data are missing with regard to their oncologic safety., Summary: This article provides an overview of the literature on currently used less invasive axillary staging procedures, the accuracy and feasibility of these procedures in clinical practice, important issues concerning axillary treatment, and issues to be addressed in ongoing or future studies., Key Messages: More evidence is needed regarding the safety of replacing standard ALND by less invasive axillary staging procedures in terms of long-term prognosis. These less invasive staging procedures not only serve to select patients who may benefit from treatment de-escalation, but also to select patients who may benefit from treatment escalation., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Many cT3 breast cancer patients are treated with mastectomy, regardless of response to neoadjuvant systemic therapy (NST). We evaluated local control of cT3 patients undergoing breast-conserving therapy (BCT) based on magnetic resonance imaging (MRI) evaluation post-NST. In addition, we analyzed predictive characteristics for positive margins after breast-conserving surgery (BCS)., Methods: All cT3 breast cancer patients who underwent BCS after NST between 2002 and 2015 at the Netherlands Cancer Institute were included. Local recurrence-free interval (LRFI) was estimated using the Kaplan-Meier method, and predictors for positive margins were analyzed using univariable analysis and multivariable logistic regression., Results: Of 114 patients undergoing BCS post-NST, 75 had negative margins, 16 had focally positive margins, and 23 had positive margins. Of those with (focally) positive margins, 12 underwent radiotherapy, 6 underwent re-excision, and 21 underwent mastectomy. Finally, 93/114 patients were treated with BCT (82%), with an LRFI of 95.9% (95% confidence interval [CI] 91.5-100%) after a median follow-up of 7 years. Predictors for positive margins in univariable analysis were hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) subtype, lobular carcinoma, and non-mass enhancement (NME) on pre-NST MRI. MRI response was not correlated to positive margins. In multivariable regression, the odds of positive margins were decreased in patients with HER2-positive (HER2+; odds ratio [OR] 0.27, 95% CI 0.10-0.73; p = 0.01) and TN tumors (OR 0.17, 95% CI 0.03-0.82; p = 0.028). A trend toward positive margins was observed in patients with NME (OR 2.38, 95% CI 0.98-5.77; p = 0.055)., Conclusion: BCT could be performed in 82% of cT3 patients in whom BCT appeared feasible on post-NST MRI. Local control in these patients was excellent. In those patients with HR+/HER2- tumors, NME on MRI, or invasive lobular carcinoma, the risk of positive margins should be considered preoperatively., (© 2021. Society of Surgical Oncology.)

Purpose: Axillary staging before neoadjuvant systemic therapy in clinically node-positive breast cancer patients with tailored axillary treatment according to the Marking Axillary lymph nodes with radioactive iodine seeds (MARI)-protocol, a protocol developed at the Netherlands Cancer Institute, is performed with [ 18 F] fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT). We aimed to assess the value of FDG-PET/CT in prone compared to standard supine position for axillary staging., Methods: We selected patients with FDG-PET/CT in supine and prone position who underwent the MARI-protocol. One hour after administration of 3.5 MBq/kg, [ 18 F]FDG-PET was performed with a low-dose prone position CT-thorax followed by a supine whole-body scan. Scans were separately reviewed by two nuclear medicine physicians and categorized by number of FDG-positive axillary lymph nodes (ALNs; cALN<4 or cALN≥4). Main outcome was axillary up- or downstaging., Results: Of 153 patients included, 24 (16%) patients were up- or downstaged at evaluation of prone images: One observer upstaged 14 patients, downstaged 3  patients and reported a higher number of ALNs (3.6 vs. 3.2, p < 0.001), while staging (4 up- and 5 downstaged) and number of ALNs (2.8 vs. 2.8) did not differ for the other. Observers agreed on up- or downstaging in only 1 (1%) patient. Irrespective of supine or prone position scanning, observers agreed on axillary staging in 124 (81%) patients and disagreed in 5 (3%). Interobserver agreement was lower with prone assessments (86%, K = 0.67) than supine (92%, K = 0.80)., Conclusions: Axillary staging with FDG-PET/CT in prone compared to supine position did not result in concordant up- or downstaging. Therefore, FDG-PET/CT in supine position only can be considered sufficient for axillary staging., (© 2021. The Author(s).)

Purpose: The presence of extensive ductal carcinoma in situ (DCIS) adjacent to HER2-positive invasive breast cancer (IBC) is often a contra-indication for breast-conserving surgery, even in case of excellent treatment response of the invasive component. Data on the response of DCIS to neoadjuvant systemic treatment (NST) are limited. Therefore, we estimated the response of adjacent DCIS to NST-containing HER2-blockade in HER2-positive breast cancer patients and assessed the association of clinicopathological and radiological factors with response., Methods: Pre-NST biopsies were examined to determine presence of DCIS in all women with HER2-positive IBC treated with trastuzumab-containing NST ± pertuzumab between 2004 and 2017 in a comprehensive cancer center. When present, multiple DCIS factors, including grade, calcifications, necrosis, hormone receptor, and Ki-67 expression, were scored. Associations of clinicopathological and radiological factors with complete response were assessed using logistic regression models., Results: Adjacent DCIS, observed in 138/316 patients with HER2-positive IBC, was eradicated after NST in 46% of patients. Absence of calcifications suspicious for malignancy on pre-NST mammography (odds ratio (OR) 3.75; 95% confidence interval (95% CI) 1.72-8.17), treatment with dual HER2-blockade (OR 2.36; 95% CI 1.17-4.75), a (near) complete response on MRI (OR 3.55; 95% CI 1.31-9.64), and absence of calcifications (OR 3.19; 95% CI 1.34-7.60) and Ki-67 > 20% in DCIS (OR 2.74; 95% CI 1.09-6.89) on pre-NST biopsy were significantly associated with DCIS response., Conclusions: As DCIS can respond to NST containing HER2-blockade, the presence of extensive DCIS in HER2-positive breast cancer before NST should not always indicate a mastectomy. The predictive factors we found could be helpful when considering breast-conserving surgery in these patients., (© 2021. The Author(s).)

Background: The nodal positivity rate after neoadjuvant chemotherapy (ypN+) in patients with clinically node-negative (cN0) breast cancer is low, especially in those with a pathological complete response of the breast. The aim of this study was to identify characteristics known before surgery that are associated with achieving ypN0 in patients with cN0 disease. These characteristics could be used to select patients in whom sentinel lymph node biopsy may be omitted after neoadjuvant chemotherapy., Methods: This cohort study included patients with cT1-3 cN0 breast cancer treated with neoadjuvant chemotherapy followed by breast surgery and sentinel node biopsy between 2013 and 2018. cN0 was defined by the absence of suspicious nodes on ultrasound imaging and PET/CT, or absence of tumour cells at fine-needle aspiration. Univariable and multivariable logistic regression analyses were performed to determine predictors of ypN0., Results: Overall, 259 of 303 patients (85.5 per cent) achieved ypN0, with high rates among those with a radiological complete response (rCR) on breast MRI (95·5 per cent). Some 82 per cent of patients with hormone receptor-positive disease, 98 per cent of those with triple-negative breast cancer (TNBC) and all patients with human epidermal growth factor receptor 2 (HER2)-positive disease who had a rCR achieved ypN0. Multivariable regression analysis showed that HER2-positive (odds ratio (OR) 5·77, 95 per cent c.i. 1·91 to 23·13) and TNBC subtype (OR 11·65, 2·86 to 106·89) were associated with ypN0 status. In addition, there was a trend toward ypN0 in patients with a breast rCR (OR 2·39, 0·95 to 6·77)., Conclusion: The probability of nodal positivity after neoadjuvant chemotherapy was less than 3 per cent in patients with TNBC or HER2-positive disease who achieved a breast rCR on MRI. These patients could be included in trials investigating the omission of sentinel node biopsy after neoadjuvant chemotherapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved.For permissions, please email: journals.permissions@oup.com.)

Background: The added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI., Methods: We performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1-4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR)., Results: Between April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45-61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27-49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72-55.89; p = 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95-21.73; p = 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87-1.00; p = 0.051)., Conclusion: The MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.

Background: The onset of the COVID-19 pandemic forced the Dutch national screening program to a halt and increased the burden on health care services, necessitating the introduction of specific breast cancer treatment recommendations from week 12 of 2020. We aimed to investigate the impact of COVID-19 on the diagnosis, stage and initial treatment of breast cancer., Methods: Women included in the Netherlands Cancer Registry and diagnosed during four periods in weeks 2-17 of 2020 were compared with reference data from 2018/2019 (averaged). Weekly incidence was calculated by age group and tumor stage. The number of women receiving initial treatment within 3 months of diagnosis was calculated by period, initial treatment, age, and stage. Initial treatment, stratified by tumor behavior (ductal carcinoma in situ [DCIS] or invasive), was analyzed by logistic regression and adjusted for age, socioeconomic status, stage, subtype, and region. Factors influencing time to treatment were analyzed by Cox regression., Results: Incidence declined across all age groups and tumor stages (except stage IV) from 2018/2019 to 2020, particularly for DCIS and stage I disease (p < 0.05). DCIS was less likely to be treated within 3 months (odds ratio [OR] wks2-8 : 2.04, OR wks9-11 : 2.18). Invasive tumors were less likely to be treated initially by mastectomy with immediate reconstruction (OR wks12-13 : 0.52) or by breast conserving surgery (OR wks14-17 : 0.75). Chemotherapy was less likely for tumors diagnosed in the beginning of the study period (OR wks9-11 : 0.59, OR wks12-13 : 0.66), but more likely for those diagnosed at the end (OR wks14-17 : 1.31). Primary hormonal treatment was more common (OR wks2-8 : 1.23, OR wks9-11 : 1.92, OR wks12-13 : 3.01). Only women diagnosed in weeks 2-8 of 2020 experienced treatment delays., Conclusion: The incidence of breast cancer fell in early 2020, and treatment approaches adapted rapidly. Clarification is needed on how this has affected stage migration and outcomes.

Background: Despite increasingly effective curative breast-conserving treatment (BCT) regimens for primary breast cancer, patients remain at risk for an ipsilateral breast tumor recurrence (IBTR). With increasing interest for repeat BCT in selected patients with IBTR, a reliable assessment of the size of IBTR is important for surgical planning., Aim: The primary aim of this study is to establish the performance in size estimation of XMG, US, and breast MRI in patients with IBTR. The secondary aim is to compare the detection of multifocality and contralateral lesions between XMG and MRI., Patients and Methods: The sizes of IBTR on mammography (XMG), ultrasound (US), and magnetic resonance imaging (MRI) in 159 patients were compared to the sizes at final histopathology. The accuracy of the size estimates was addressed using Pearson's coefficient and Bland-Altman plots. Secondary outcomes were the detection of multifocality and contralateral lesions between XMG and MRI., Results: Both XMG and US significantly underestimated the tumor size by 3.5 and 4.8 mm, respectively, while MRI provided accurate tumor size estimation with a mean underestimation of 1.1 mm. The sensitivity for the detection of multifocality was significantly higher for MRI compared to XMG (25.5% vs. 5.5%). A contralateral malignancy was found in 4.4% of patients, and in 1.9%, it was detected by MRI only., Conclusion: The addition of breast MRI to XMG and US in the preoperative workup of IBTR allows for more accurate size estimation. MRI provides a higher sensitivity for the detection of multifocality compared to XMG.

Objectives: To improve quality in breast cancer care, large numbers of quality indicators are collected per hospital, but benchmarking remains complex. We aimed to assess the validity of indicators, develop a textbook outcome summary measure, and compare case-mix adjusted hospital performance., Methods: From a nationwide population-based registry, all 79 690 nonmetastatic breast cancer patients surgically treated between 2011 and 2016 in 91 hospitals in The Netherlands were included. Twenty-one indicators were calculated and their construct validity tested by Spearman's rho. Between-hospital variation was expressed by interquartile range (IQR), and all valid indicators were included in the summary measure. Standardized scores (observed/expected based on case mix) were calculated as above (>100) or below (<100) expected. The textbook outcome was presented as a continuous and all-or-none score., Results: The size of between-hospital variation varied between indicators. Sixteen (76%) of 21 quality indicators showed construct validity, and 13 were included in the summary measure after excluding redundant indicators that showed collinearity with others owing to strong construct validity. The median all-or-none textbook outcome score was 49% (IQR 42%-54%) before and 49% (IQR 48%-51%) after case-mix adjustment. From the total of 91 hospitals, 3 hospitals were positive (3%) and 9 (10%) were negative outliers., Conclusions: The textbook outcome summary measure showed discriminative ability when hospital performance was presented as an all-or-none score. Although indicator scores and outlier hospitals should always be interpreted cautiously, the summary measure presented here has the potential to improve Dutch breast cancer quality indicator efforts and could be implemented to further test its validity, feasibility, and usefulness., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objectives: Hospital comparisons to improve quality of care require valid and reliable quality indicators. We aimed to test the validity and reliability of 6 breast cancer indicators by quantifying the influence of case-mix and random variation., Methods: The nationwide population-based database included 79 690 patients with breast cancer from 91 Dutch hospitals between 2011 and 2016. The indicator-scores calculated were: (1) irradical breast-conserving surgery (BCS) for invasive disease, (2) irradical BCS for ductal carcinoma-in-situ, (3) breast contour-preserving treatment, (4) magnetic resonance imaging (MRI) before neo-adjuvant chemotherapy, (5) radiotherapy for locally advanced disease, and (6) surgery within 5 weeks from diagnosis. Case-mix and random variation adjustments were performed by multivariable fixed and random effect logistic regression models. Rankability quantified the between-hospital variation, representing unexplained differences that might be the result of the level of quality of care, as low (<50%), moderate (50%-75%), or high (>75%)., Results: All of the indicators showed between-hospital variation with wide (interquartile) ranges. Case-mix adjustment reduced variation in indicators 1 and 3 to 5. Random variation adjustment (further) reduced the variation for all indicators. Case-mix and random variation adjustments influenced the indicator-scores of individual hospitals and their ranking. Rankability was poor for indicator 1, 2, and 5, and moderate for 3, 4, and 6., Conclusions: The 6 indicators lacked validity and/or reliability to a certain extent. Although measuring quality indicators may stimulate quality improvement in general, comparisons and judgments of individual hospital performance should be made with caution if based on indicators that have not been tested or adjusted for validity and reliability, especially in benchmarking., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: The incidence and clinical significance of multifocality in ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) are unclear. With growing interest in repeat BCT, this information has become of importance. This study aimed to gain insight in the incidence of multifocality in IBTR, to identify patient- and tumor-related predicting factors and to investigate the prognostic significance of multifocality., Methods: Two hundred and fifteen patients were included in this analysis. All had an IBTR after BCT and were treated by salvage mastectomy and appropriate adjuvant therapy. Predictive tumor- and patient-related factors for multifocality in IBTR were identified using X2 test and univariate logistic regression analyses. Prognostic outcomes were calculated using Kaplan Meier analysis and compared using the log rank test., Results: Multifocality was present in 50 (22.9%) of IBTR mastectomy specimens. Axillary positivity in IBTR was significantly associated with multifocality in IBTR. Chest wall re-recurrences occurred more often after multifocal IBTR (14% versus 7% after unifocal IBTR, p = 0.120). Regional re-recurrences did not differ significantly between unifocal and multifocal IBTR (8% vs. 6%, p = 0.773). Distant metastasis after salvage surgery occurred more frequently after multifocal IBTR (15% vs. 24%, p = 0.122). Overall survival was 132 months after unifocal IBTR and 112 months after multifocal IBTR (p = 0.197)., Conclusion: The prevalence of multifocality in IBTR is higher than in primary breast cancer. Axillary positivity in IBTR was associated with a multifocal IBTR. Chest wall re-recurrences and distant metastasis were, although not statistically significant, more prevalent after multifocal IBTR., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)