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Purpose: Ductal-carcinoma in situ (DCIS) is a pre-invasive form of breast cancer with good prognosis. Follow-up guidelines in the Netherlands are currently the same as for invasive breast cancer. Due to fear of invasive breast cancer or recurrence, it is hypothesized that follow-up for DCIS after treatment is more intense in practice resulting in potentially unnecessary high costs. This study investigates the follow-up in practice for patients with DCIS compared to the recommendations in order to inform clinicians and policy makers how to utilize these guidelines., Methods: Patients diagnosed with pure DCIS between 2004 and 2014 were followed up until 2018. Information on duration and frequency of follow-up visits, reasons and decision makers for shortening, and prolonging follow-up was collected. Prolonged follow-up was defined as deviation from the Dutch guideline: more than 5 years of follow-up and older than 60 years., Results: Of the 227 patients the mean number of visits per year was 1.4 and mean years of follow-up was 6.0. Thirty-three percent had prolonged follow-up and 26% shorter follow-up than recommended. A majority (78%) of decision for prolonged follow-up was being made by clinicians., Conclusion: Follow-up duration is in almost half of patients with DCIS according to guidelines and with most prolonged follow-up only up to a year longer than recommended. In most cases suspicious findings and the timing of the population screening program appeared to cause prolonged follow-up. If accepted by patients and clinicians, future DCIS specific guidelines should address these reasons and tailor to the individual risks., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The first aim of this study was to examine trends in the risk of ipsilateral invasive breast cancer (iIBC) after breast-conserving surgery (BCS) of ductal carcinoma in situ (DCIS). A second aim was to analyse the association between DCIS grade and the risk of iIBC following BCS., Patients and Methods: In this population-based, retrospective cohort study, the Netherlands Cancer Registry collected information on 25,719 women with DCIS diagnosed in the period 1989-2021 who underwent BCS. Of these 19,034 received adjuvant radiotherapy (RT). Kaplan-Meier analyses and Cox regression models were used., Results: A total of 1135 patients experienced iIBC. Ten-year cumulative incidence rates of iIBC for patients diagnosed in the periods 1989-1998, 1999-2008 and 2009-2021 undergoing BCS without RT, were 12.6%, 9.0% and 5.0% (P < 0.001), respectively. For those undergoing BCS with RT these figures were 5.7%, 3.7% and 2.2%, respectively (P < 0.001). In the multivariable analyses, DCIS grade was not associated with the risk of iIBC., Conclusion: Since 1989 the risk of iIBC has decreased substantially and has become even lower than the risk of invasive contralateral breast cancer. No significant association of DCIS grade with iIBC was found, stressing the need for more powerful prognostic factors to guide the treatment of DCIS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: In up to 72 % of HER2+ invasive breast cancer (IBC), a ductal carcinoma in situ (DCIS) component is present. The presence of DCIS is associated with increased positive surgical margins after breast-conserving surgery (BCS). The aim of this study was to assess surgical margins, recurrence and survival in a nationwide cohort of HER2+ IBC with versus without a DCIS component, treated with neoadjuvant systemic therapy (NST) and BCS., Materials and Methods: Women diagnosed with HER2+ IBC treated with NST and BCS, between 2010 and 2019, were selected from the Netherlands Cancer Registry and linked to the Dutch Nationwide Pathology Databank. Kaplan-Meier and Cox regression analyses were performed to determine locoregional recurrence rate (LRR) and overall survival (OS) and associated clinicopathological variables. Surgical outcomes and prognosis were compared between IBC only and IBC+DCIS., Results: A total of 3056 patients were included: 1832 with IBC and 1224 with IBC+DCIS. Patients with IBC+DCIS had significantly more often positive surgical margins compared to IBC (12.8 % versus 4.9 %, p < 0.001). Five-year LRR was significantly higher in patients with IBC+DCIS compared to IBC (6.8 % versus 3.6 %, p < 0.001), but the presence of DCIS itself was not significantly associated with LRR after adjusting for confounders in multivariable analysis. Five-year OS did not differ between IBC+DCIS and IBC (94.9 % versus 95.7 %, p = 0.293)., Conclusion: The presence of DCIS is associated with higher rates of positive surgical margins, but not with LRR and lower OS when adjusted for confounders. Further research is necessary to adequately select IBC+DCIS patients for BCS after NST., Competing Interests: Declaration of competing interest Prof. Dr. Smidt reports grants from Nutricia and Servier Pharmaceuticals for microbiome research in colorectal cancer, and use of material from Illumina, not related to this study. Dr. T. van Nijnatten received institutional grant support from Bayer, and speaker honoraria from GE Healthcare and Bayer, not related to this study. L. Kooreman reports consulting fees from Novartis and educational fees from SCEM, not related to this study. All author authors report no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Insight into the aggressiveness of potential breast cancers found in screening may optimize recall decisions. Specific growth rate (SGR), measured on mammograms, may provide valuable prognostic information. This study addresses the association of SGR with prognostic factors and overall survival in patients with invasive carcinoma of no special type (NST) from a screened population., Methods: In this historic cohort study, 293 women with NST were identified from all participants in the Nijmegen screening program (2003-2007). Information on clinicopathological factors was retrieved from patient files and follow-up on vital status through municipalities. On consecutive mammograms, tumor volumes were estimated. After comparing five growth functions, SGR was calculated using the best-fitting function. Regression and multivariable survival analyses described associations between SGR and prognostic factors as well as overall survival., Results: Each one standard deviation increase in SGR was associated with an increase in the Nottingham prognostic index by 0.34 [95% confidence interval (CI): 0.21-0.46]. Each one standard deviation increase in SGR increased the odds of a tumor with an unfavorable subtype (based on histologic grade and hormone receptors; odds ratio 2.14 [95% CI: 1.45-3.15]) and increased the odds of diagnosis as an interval cancer (versus screen-detected; odds ratio 1.57 [95% CI: 1.20-2.06]). After a median of 12.4 years of follow-up, 78 deaths occurred. SGR was not associated with overall survival (hazard ratio 1.12 [95% CI: 0.87-1.43])., Conclusions: SGR may indicate prognostically relevant differences in tumor aggressiveness if serial mammograms are available. A potential association with cause-specific survival could not be determined and is of interest for future research., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.)

Introduction: There have been several developments in the treatment of HER2-overexpressing metastatic breast cancer. However, pivotal trials mainly included younger and healthier patients, resulting in a lack of information about the benefits and harms of treatment for most older patients. The aim of this study was to provide an overview of the differences in treatment allocation and survival outcomes over time between younger and older patients with HER2-overexpressing metastatic breast cancer., Materials and Methods: All patients from the Netherlands Cancer Registry with de novo metastatic breast cancer between 2005 and 2021 were included. Patients were divided into three age groups: <65, 65-74, and ≥ 75 years. Changes in treatment allocation were graphically depicted over time. Cox proportional hazard models were used to calculate overall survival and Poisson models for relative survival., Results: Overall, 2,722 patients were included. Between 2005 and 2021, the use of targeted therapy as first-line treatment increased for all age groups (<65 years from 33.8% to 90.6%, p < 0.001; 65-74 years from 29.2% to 86.5%, p = 0.001; ≥75 years from 4.3% to 55.8%, p < 0.001). Use of chemotherapy as first-line treatment also increased for all age groups (<65 years from 73.5% to 89.8%, p < 0.001; 65-74 years from 50.0% to 78.4%, p = 0.01; ≥75 years from 8.7% to 37.2%, p = 0.04). Although not statistically significant, the use of endocrine therapy, both as monotherapy and in combination with targeted therapy in the first line, decreased (<65 years 19.1% to 5.5%, p < 0.001; 65-74 years 25.0% to 13.5%, p = 0.03; ≥75 years 65.2% to 37.2%, p = 0.16). Changes in relative and overall survival were similar and improved in all age groups, but most in the youngest age group (relative excess risk [RER] 0.93, 95% confidence interval [CI] 0.91-0.94 per year, p < 0.001), and least in patients ≥75 (RER 0.96, 95% CI 0.93-0.98 per year, p = 0.001)., Discussion: The use of first-line chemotherapy and targeted therapy increased in all age groups, while the use of endocrine therapy decreased over time. Nevertheless, the uptake of chemotherapy and targeted therapies was substantially slower in the oldest age group. Overall survival and relative survival improved for all age groups, but these improvements were smaller in the older age groups., 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: Follow-up guidelines barely diverge from a one-size-fits-all approach, even though the risk of recurrence differs per patient. However, the personalization of breast cancer care improves outcomes for patients. This study explores the variation in follow-up pathways in the Netherlands using real-world data to determine guideline adherence and the gap between daily practice and risk-based surveillance, to demonstrate the benefits of personalized risk-based surveillance compared with usual care., Methods: Patients with stage I-III invasive breast cancer who received surgical treatment in a general hospital between 2005 and 2020 were selected from the Netherlands Cancer Registry and included all imaging activities during follow-up from hospital-based electronic health records. Process analysis techniques were used to map patients and activities to investigate the real-world utilisation of resources and identify the opportunities for improvement. The INFLUENCE 2.0 nomogram was used for risk prediction of recurrence., Results: In the period between 2005 and 2020, 3478 patients were included with a mean follow-up of 4.9 years. In the first 12 months following treatment, patients visited the hospital between 1 and 5 times (mean 1.3, IQR 1-1) and received between 1 and 9 imaging activities (mean 1.7, IQR 1-2). Mammogram was the prevailing imaging modality, accounting for 70% of imaging activities. Patients with a low predicted risk of recurrence visited the hospital more often., Conclusions: Deviations from the guideline were not in line with the risk of recurrence and revealed a large gap, indicating that it is hard for clinicians to accurately estimate this risk and therefore objective risk predictions could bridge this gap., (© 2024. The Author(s).)

Background: Several factors may increase the risk of recurrence of patients diagnosed with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). We aim to determine the proportion of patients with high-risk HR+/HER2- BC within the total HR+/HER2- BC cohort and compare their systemic treatments and survival rates with those of patients with low- and intermediate-risk HR+/HER2- BC and triple-negative (TN) BC., Patients and Methods: Women diagnosed with nonmetastatic invasive HR+/HER2- BC and TNBC in the Netherlands between 2011 and 2019 were identified from the Netherlands Cancer Registry. Patients with HR+/HER2- BC were categorised according to risk profile, defined by nodal status, tumour size, and histological grade. High-risk HR+/HER2- BC was defined by either four or more positive lymph nodes or one to three positive lymph nodes with a tumour size of ≥5 cm or a histological grade 3 tumour. Overall survival (OS) and relative survival (RS) were calculated using the Kaplan-Meier and Pohar-Perme method., Results: In this study of 87 455 patients with HR+/HER2- BC, 44 078 (50%) patients were diagnosed with low risk, 28 452 (33%) with intermediate risk, and 11 285 (13%) with high-risk HR+/HER2- BC. In 3640 (4%) patients, the risk profile could not be defined. Endocrine therapy and chemotherapy were used in 38% and 7% of low-risk, 90% and 47% of intermediate-risk, and 94% and 73% of high-risk patients, respectively. The 10-year OS and RS rates were 84.1% [95% confidence interval (95% CI) 83.5% to 84.7%] and 98.7% (95% CI 97.3% to 99.4%) in low-risk, 75.1% (95% CI 74.2% to 76.0%) and 91.7% (95% CI 89.7% to 93.3%) in intermediate-risk, and 63.4% (95% CI 62.0% to 64.7%) and 72.3% (70.1% to 74.3%) in high-risk patients. The 10-year OS and RS rates of 12 689 patients with TNBC were 69.7% (95% CI 68.6% to 70.8%) and 79.1% (95% CI 77.0% to 80.9%), respectively., Conclusion: The poor prognosis of patients with high-risk HR+/HER2- BC highlights the need for a better acknowledgement of this subgroup and supports ongoing clinical trials aimed at optimising systemic therapy., (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.)

Background: Comparing the impact of the COVID-19 pandemic on the incidence of newly diagnosed breast tumors and their tumor stage between the Netherlands and Norway will help us understand the effect of differences in governmental and social reactions towards the pandemic., Methods: Women newly diagnosed with breast cancer in 2017-2021 were selected from the Netherlands Cancer Registry and the Cancer Registry of Norway. The crude breast cancer incidence rate (tumors per 100,000 women) during the first (March-September 2020), second (October 2020-April 2021), and Delta COVID-19 wave (May-December 2021) was compared with the incidence rate in the corresponding periods in 2017, 2018, and 2019. Incidence rates were stratified by age group, method of detection, and clinical tumor stage., Results: During the first wave breast cancer incidence declined to a larger extent in the Netherlands than in Norway (27.7% vs. 17.2% decrease, respectively). In both countries, incidence decreased in women eligible for screening. In the Netherlands, incidence also decreased in women not eligible for screening. During the second wave an increase in the incidence of stage IV tumors in women aged 50-69 years was seen in the Netherlands. During the Delta wave an increase in overall incidence and incidence of stage I tumors was seen in Norway., Conclusion: Alterations in breast cancer incidence and tumor stage seem related to a combined effect of the suspension of the screening program, health care avoidance due to the severity of the pandemic, and other unknown factors., Competing Interests: Declaration of Competing Interest SS reports personal fees from the External Evaluation Committee: Public health master University of Nicosia and the Supervisory Board of PALGA (national Pathology laboratory Archive). VCGTH receives funding from AstraZeneca, E Lilly, Gilead, Novartis, Pfizer, and Roche. JW receives funding from Cancer Research UK, KWF Dutch Cancer Society, ZonMW, and AVL Investment Fund. The other authors have no relevant conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The validity of the PREDICT breast cancer prognostic model is unclear for young patients without adjuvant systemic treatment. This study aimed to validate PREDICT and assess its clinical utility in young women with node-negative breast cancer who did not receive systemic treatment., Methods: We selected all women from the Netherlands Cancer Registry who were diagnosed with node-negative breast cancer under age 40 between 1989 and 2000, a period when adjuvant systemic treatment was not standard practice for women with node-negative disease. We evaluated the calibration and discrimination of PREDICT using the observed/expected (O/E) mortality ratio, and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, we compared the potential clinical utility of PREDICT for selectively administering chemotherapy to the chemotherapy-to-all strategy using decision curve analysis at predefined thresholds., Results: A total of 2264 women with a median age at diagnosis of 36 years were included. Of them, 71.2% had estrogen receptor (ER)-positive tumors and 44.0% had grade 3 tumors. Median tumor size was 16 mm. PREDICT v2.2 underestimated 10-year all-cause mortality by 33% in all women (O/E ratio:1.33, 95%CI:1.22-1.43). Model discrimination was moderate overall (AUC 10-year :0.65, 95%CI:0.62-0.68), and poor for women with ER-negative tumors (AUC 10-year :0.56, 95%CI:0.51-0.62). Compared to the chemotherapy-to-all strategy, PREDICT only showed a slightly higher net benefit in women with ER-positive tumors, but not in women with ER-negative tumors., Conclusions: PREDICT yields unreliable predictions for young women with node-negative breast cancer. Further model updates are needed before PREDICT can be routinely used in this patient subset., Competing Interests: Declaration of Competing Interest Sabine C. Linn has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Roche and Sanofi, and has received unrestricted institutional research support or unrestricted educational funding from Agendia, Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eurocept Pharmaceuticals, Genentech, Immunomedics (now Gilead), Merck, Roche, Sanofi and TESARO (now GSK), and has a pending patent application for a BRCA-like ovarian cancer classifier. Paul J. van Diest has a pending patent application for DDX3 as a biomarker for cancer and its related methods. Gabe Sonke has received institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche and Seagen. Other authors claim no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With improved survival of cancer patients, we increasingly encounter infrequent metastatic locations. While for the common metastatic locations both prognostic information as well as evidence-based guidelines are available, for rare locations we have to rely on anecdotal case reports, the value of which is currently unknown. Therefore, we performed a systemic literature review and compare the results with a large national real-life cohort focussed on breast cancer patients with colorectal metastases. We performed a systematic literature search for breast cancer patients with colorectal metastases. Autopsy studies were excluded. Data on stage, histological factors, treatment and outcome were extracted. All identified cases were analysed as individual patients. The real-life cohort was extracted from the nationwide Dutch pathology databank. Linkage with the Netherlands Cancer Registry provided clinical characteristics, treatment and outcome data. Survival analyses and univariate regression were performed to identify relevant features for future treatment decisions. We identified 308 patients from 207 studies in the literature, and 454 patients in the real-life cohort. Colorectal metastases were the first metastatic event in 42.5% and 47.0% respectively. Cohorts were comparable for age, gender, location and hormone status, but differed in tumour type, stage and treatment. The time to colorectal metastases was similar in both cohorts (median of 68 months), and was dependent on presence of other metastases, nodal status, and primary breast surgery. The median overall survival after development of colorectal metastases was 20.6 months (95%CI 18.0-23.1 months). Despite a potential publication bias and lack of complete data for patients in the case report series, we have shown that an extensive systematic review can provide data that are comparable to real-life data, which can be used for decision-making and informing patients. Colorectal metastases are a late event in breast cancer patients, that is not associated with a detrimental survival., (© 2023. The Author(s).)

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.)

During the last decade completion axillary lymph node dissection (cALND) was gradually omitted in sentinel lymph node positive (SLN+) breast cancer patients. However, adoption varies among hospitals. We analyzed factors associated with the omission of cALND in all Dutch SLN+ patients. As one of the focus hospital-related factors we defined "innovative" as the percentage of gene-expression profile (GEP) deployment within the indicated group of patients per hospital as a proxy for early adoption of innovations. cT1-2N0M0 SLN+ patients treated between 2011 and 2018 were selected from the Netherlands Cancer Registry. Hospitals were defined to be innovative based on their GEP use. Multivariable logistic regression (MLR) was performed to assess the relationship between innovative capacity, patient-, treatment- and hospital-related characteristics and cALND performance. 14 317 patients were included. Treatment in a hospital with high innovative capacity was associated with a lower probability of receiving cALND (OR 0.69, OR 0.46 and OR 0.35 in modestly, fairly and very innovative, respectively). Other factors associated with a lower probability of receiving a cALND were age 70 and 79 years and ≥79 years (ORs 0.59 [95% CI: 0.50-0.68] and 0.21 [95% CI: 0.17-0.26]) and treatment in an academic hospital (OR 0.41 [95% CI: 0.33-0.51]). Factors associated with an increased probability of undergoing cALND were HR-/HER2- tumors (OR 1.46 [95% CI: 1.19-1.80]), macrometastatic lymph node involvement (OR 6.37 [95% CI: 5.70-7.13]) and mastectomy (OR 4.57 [95% CI: 4.09-5.10]). Patients treated in a hospital that early adopted innovations were less likely to receive cALND. Our findings endorse the need for studies on barriers and facilitators of implementing innovations., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Conclusions and Relevance: This study found that CDK4/6 inhibitors rapidly reached many eligible patients with metastatic breast cancer and were adopted gradually over time in the Netherlands. Adoption of innovative medicines may be further optimized, and better transparency of the availability of new medicines during different phases of the postapproval access pathway is needed., Design, Setting, and Participants: This cohort study reviewed approval and reimbursement decisions of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib and estimated the number of patients with metastatic breast cancer who were eligible for these medicines compared with the actual use in clinical practice. The study used nationwide claims data that were obtained from the Dutch Hospital Data. Claims and early access data for patients with hormone receptor-positive and ERBB2 (formerly HER2)-negative metastatic breast cancer who were treated with CDK4/6 inhibitors from November 1, 2016, to December 31, 2021, were included., Importance: The number of new cancer medicines that are being approved by regulatory agents is increasing exponentially. Yet little is known about the pace at which these medicines reach eligible patients in daily clinical practice during different phases of the postapproval access pathway., Main Outcomes and Measures: Description of the postapproval access pathway, monthly number of patients who were treated with CDK4/6 inhibitors in clinical practice, and estimated number of patients who were eligible for treatment. Aggregated claims data were used, and patient characteristics and outcomes data were not collected., Objective: To describe the entire postapproval access pathway of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in the Netherlands, from regulatory approval to reimbursement and to investigate the adoption of these medicines in clinical practice among patients with metastatic breast cancer., Results: Three CDK4/6 inhibitors have received European Union-wide regulatory approval for the treatment of HR-positive and ERBB2-negative metastatic breast cancer since November 2016. In the Netherlands, the number of patients who have been treated with these medicines increased to approximately 1847 (based on 1 624 665 claims over the entire study period) from approval to the end of 2021. Reimbursement for these medicines was granted between 9 and 11 months after approval. While awaiting reimbursement decisions, 492 patients received palbociclib, the first approved medicine of this class, via an expanded access program. By the end of the study period, 1616 patients (87%) were treated with palbociclib, whereas 157 patients (7%) received ribociclib, and 74 patients (4%) received abemaciclib. The CKD4/6 inhibitor was combined with an aromatase inhibitor in 708 patients (38%) and with fulvestrant in 1139 patients (62%). The pattern of use over time appeared to be somewhat lower compared with the estimated number of eligible patients (1847 vs 1915 in December 2021), especially in the first 2.5 years after approval.

Purpose: Follow-up for breast cancer survivors consists of after care and surveillance. The benefits of routine surveillance visits remain debatable. In this study we compared the severity of locoregional recurrences (LRRs) and the subsequent risk of a distant metastasis (DM) between LRRs detected at routine and interval visits., Methods: Women diagnosed with early breast cancer between 2003 and 2008 in one of the 15 participating hospitals, and who developed a LRR as first event after primary treatment, were selected from the Netherlands Cancer Registry (Cohort A). Chi-squared tests were used to compare the severity of routine- and interval-detected local recurrences (LRs) and regional recurrences (RRs), using tumor size, tumor grade, and number of positive lymph nodes. Data on the development of a subsequent DM after a LRR were available for a subset of patients (Cohort B). Cohort B was used to estimate the association between way of LRR-detection and risk of a DM., Results: Cohort A consisted of 109 routine- and 113 interval-LRR patients. The severity of routine-detected LRs or RRs and interval-detected LRs or RRs did not significantly differ. Cohort B consisted of 66 routine- and 61 interval-LRR patients. Sixteen routine- (24%) and 17 (28%) interval-LRR patients developed a DM. After adjustment, way of LRR-detection was not significantly associated with the risk of a DM (hazard ratio: 1.22; 95% confidence interval: 0.49-3.06)., Conclusion: The current study showed that routine visits did not lead to less severe LRRs and did not decrease the risk of a subsequent DM., (© 2022. The Author(s).)

Introduction: Each year, around 600 young (<40 years) breast cancer (BC) patients are registered in the national NABON Breast Cancer Audit (NBCA). The aim of this study is to compare patient and treatment characteristics of young and older age BC patients over time with a focus on outcome of quality indicators (QIs). Furthermore, we analysed whether de-escalation trends of treatment can be recognized to the same degree in both patient groups., Material and Methods: From October 2011 to October 2020 all patients treated for stage I-III invasive BC were included. Tumour characteristics, treatment variables and outcome of QIs of two age categories young (<40 years) and older patient (≥40 years) were analysed., Results: In total 114,700 patients were included: 4.6% young patients and 95.4% older patients. Young patients more often presented with a palpable mass, higher stage, and triple-negative BC. Overall, young patients more often started with neoadjuvant systemic treatment (NST) (54.3% vs. 18.6%) and a greater proportion of the young patients retained their breast contour after surgery (73.5% vs. 69.3%). De-escalation trends such as decrease in axillary lymph node dissections and in the use of boost were observed. The omission of radiation treatment after breast conserving surgery was only observed in older patients., Conclusion: Although this study shows that young women more often present with unfavourable tumours, therapeutic procedures are performed with a higher adherence to the QIs than for older patients and young women do benefit from some de-escalation trends to the same extend as older patients., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: With the increasing complexity of modern oncological patient management and the growing amount of information needed from the pathologist, traditional narrative pathology reports (NR) do not suffice. Standardized synoptic reporting (SR) increases both completeness and readability. In the Netherlands SR for breast cancer was introduced in 2009. We explore the impact of synoptic reporting on breast cancer care., Methods: Using data from the Netherlands Cancer Registry and Dutch Nationwide Pathology Databank, a retrospective population-based cohort study was performed. Data of breast cancer resections from 2007 to 2014 were collected to compare NR and SR for all outcome measures. Kaplan-Meier analyses and log-rank testing were used to estimate overall survival., Results: Over time there was an increase from 12% to 78.9% in the use of SR. SR resulted in higher completeness of pathology reports, particularly for hormone and HER2/neu receptor status. Although there was no difference in the administration of antihormonal therapy, anti-HER2 treatment was more frequently administered to eligible patients in the SR group. An effect on overall survival could not yet be confirmed on multivariate analysis., Conclusions: We demonstrate that SR has led to more complete pathology reports, which meets the needs for precision of information in breast cancer care. This is expected to improve communication and discussions between specialists regarding parameters important for adjuvant breast cancer treatment decisions. SR thereby improves breast cancer care and leads to improved allocation of treatment based on pathologic parameters and more personalized treatment regimens., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

Background and Objectives: To evaluate the representativeness of Dutch patients participating in the European Organization for Research and Treatment of Cancer EORTC boost-no-boost trial to the target breast cancer patient population., Methods: All female breast cancer patients diagnosed between 1989 and 1996, aged ≤70 years, treated with breast-conserving surgery and radiation therapy, were selected from the Netherlands Cancer Registry (NCR) and linked to the EORTC trial database. Baseline characteristics were compared between trial and non-trial participants, for the Dutch population and according to seven participating institutions. Kaplan-Meier curves and multivariable Cox regression were used to explore potential heterogeneity in overall survival between low, medium and high-volume institutes., Results: Overall, 20,880 patients were identified from the NCR: 2,445 of 2,602 (94%) trial participants could be linked, and 18,435 were treated outside the trial. Trial participants had similar age, morphology, topography, laterality and socioeconomic status as non-trial participants, but more often stage I (62.7% vs. 56.4%) tumours and less often adjuvant treatment (22.9% vs. 26.5%). Crude 20-year survival ranged from 52.5% to 57.4%, without significant differences in multivariable analyses., Conclusion: This case study showed that participants in the boost-no-boost trial well represented the Dutch target population. Data linkage comes with challenges, but can close the gap between research and clinical practice., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Although adjuvant systemic therapy (AST) helps increase breast cancer-specific survival (BCSS), there is a growing concern for overtreatment. By estimating the expected BCSS of AST using PREDICT, this study aims to quantify the number of patients treated with AST without benefit to provide estimates of overtreatment., Methods: Data of all non-metastatic unilateral breast cancer patients diagnosed in 2015 were retrieved from cancer registries from The Netherlands and the USA. The PREDICT tool was used to estimate AST survival benefit. Overtreatment was defined as the proportion of patients that would have survived regardless of or died despite AST within 10 years. Three scenarios were evaluated: actual treatment, and recommendations by the Dutch or USA guidelines., Results: 59.5% of Dutch patients were treated with AST. 6.4% (interquartile interval [IQI] = 2.5, 8.2%) was expected to survive at least 10 years due to AST, leaving 93.6% (IQI = 91.8, 97.5%) without AST benefit (overtreatment). The lowest expected amount of overtreatment was in the targeted and chemotherapy subgroup, with 86.5% (IQI = 83.4, 89.6%) overtreatment, and highest in the only endocrine treatment subgroup, with 96.7% (IQI = 96.0, 98.1%) overtreatment. Similar results were obtained using data from the USA, and guideline recommendations., Conclusion: Based on PREDICT, AST prevents 10-year breast cancer death in 6.4% of the patients treated with AST. Consequently, AST yields no survival benefit to many treated patients. Especially improved personalization of endocrine therapy is relevant, as this therapy is widely used and is associated with the highest amount of overtreatment., (© 2022. The Author(s).)

Background: Associations between socioeconomic status (SES) and breast cancer survival are most pronounced in young patients. We further investigated the relation between SES, subsequent recurrent events and mortality in breast cancer patients < 40 years. Using detailed data on all recurrences that occur between date of diagnosis of the primary tumor and last observation, we provide a unique insight in the prognosis of young breast cancer patients according to SES., Methods: All women < 40 years diagnosed with primary operated stage I-III breast cancer in 2005 were selected from the nationwide population-based Netherlands Cancer Registry. Data on all recurrences within 10 years from primary tumor diagnosis were collected directly from patient files. Recurrence patterns and absolute risks of recurrence, contralateral breast cancer (CBC) and mortality - accounting for competing risks - were analysed according to SES. Relationships between SES, recurrence patterns and excess mortality were estimated using a multivariable joint model, wherein the association between recurrent events and excess mortality (expected mortality derived from the general population) was included., Results: We included 525 patients. The 10-year recurrence risk was lowest in high SES (18.1%), highest in low SES (29.8%). Death and CBC as first events were rare. In high, medium and low SES 13.2%, 15.3% and 19.1% died following a recurrence. Low SES patients had shorter median time intervals between diagnosis, first recurrence and 10-year mortality (2.6 and 2.7 years, respectively) compared to high SES (3.5 and 3.3 years, respectively). In multivariable joint modeling, high SES was significantly related to lower recurrence rates over 10-year follow-up, compared to low SES. A strong association between the recurrent event process and excess mortality was found., Conclusions: High SES is associated with lower recurrence risks, less subsequent events and better prognosis after recurrence over 10 years than low SES. Breast cancer risk factors, adjuvant treatment adherence and treatment of recurrence may possibly play a role in this association., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Delayed breast reconstruction (DBR) is a valid option for postmastectomy breast cancer patients who have a desire for breast reconstruction but are not considered suitable for immediate breast reconstruction (IBR). The objective of this study was to investigate the clinical practice and predictors of the use of DBR in the Netherlands., Methods: Stage I-III breast cancer patients diagnosed from January to March 2012 and treated with mastectomy were selected from the Netherlands Cancer Registry. Routinely collected patient, tumor, treatment and hospital characteristics were complemented with data about DBR up to 2018. Multivariable logistic regression analyses were performed to identify factors independently associated with postmastectomy DBR. Factors associated with time to DBR were identified through Cox regression analyses., Results: Of all patients who underwent mastectomy (n = 1,415), 10.2% underwent DBR. DBR patients more often received autologous reconstruction compared to IBR patients (37.5% vs 6.2%, p < 0.001). Age below 50 years (age < 35 OR 15.55, age 35-49 OR 4.18) and neoadjuvant and adjuvant chemotherapy (OR 2.59 and OR 2.83, respectively) were significantly associated with DBR. Mean time to DBR was 2.4 years [range 1-6 years]. Time to DBR was significantly associated with age < 35 years (HR 2.22), and a high hospital volume (HR 1.87)., Discussion: The use of DBR after mastectomy could not be fully explained by age below 50 years, chemotherapy, and hospital volume. Treatment with radiotherapy and adjuvant chemotherapy increased time to DBR. More information about patient preferences is needed to understand the use and timing of reconstruction., (© 2021. The Author(s).)

In August 2017, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have been reimbursed in the Netherlands for patients with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC). This study evaluates the implementation of CDK4/6 inhibitors and changes in treatment choices in the Netherlands. All patients diagnosed with HR+/HER2- ABC in 2009 to 2018 in seven hospitals were selected from the Southeast Netherlands Advanced Breast cancer (SONABRE) registry. The 2-year cumulative use of CDK4/6 inhibitors since reimbursement date (August 2017) was assessed using competing-risk methodology in two cohorts. The first cohort included patients with ABC diagnosis between August 2017 and December 2018. The second cohort included patients with ABC diagnosis between 2009 and August 2017, and still alive on August 1, 2017. In addition, treatment choices in the first three lines of therapy in calendar years 2009 to 2018 were evaluated for the total study population. Among patients diagnosed since August 2017 (n = 214), 50% (95% confidence interval [CI] = 43-57) received CDK4/6 inhibitors within 2 years beyond diagnosis. Of eligible patients diagnosed before August 2017 (n = 417), 31% (95% CI = 27-36) received CDK4/6 inhibitors within 2 years following reimbursement. Another 20% of both cohorts are still CDK4/6 inhibitor naïve and on first-line therapy. The use of chemotherapy decreased in first two lines of therapy between 2009 and 2018 (first-line: 29%-13%; second-line: 26%-19%). The implementation rate of CDK4/6 inhibitors since reimbursement is currently 50% within 2 years beyond diagnosis and is expected to increase further. The implementation of targeted therapy decreased the use of chemotherapy as first-line therapy., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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 transition from wire-guided localization (WGL) of non-palpable breast cancer to other localization techniques. Multiple prospective studies have sought to establish superior clinical outcomes for radioactive-seed localization (RSL), but consistent and congruent evidence is missing., Methods: In this study, female patients with breast cancer operated with breast-conserving surgery after tumour localization of a non-palpable breast cancer or ductal carcinoma in situ (DCIS) were included. The cohort was identified from the nationwide Netherlands Breast Cancer Audit conducted between 2013 and 2018. Trends in localization techniques were analysed. Univariable and multivariable analyses were performed to assess the association between the localization technique and the probability of a reoperation., Results: A total of 28 370 patients were included in the study cohort. The use of RSL increased from 15.7 to 61.1 per cent during the study years, while WGL decreased from 75.4 to 31.6 per cent. The localization technique used (RSL versus WGL) was not significantly associated with the odds of a reoperation, regardless of whether the lesion was DCIS (odds ratio 0.96 (95 per cent c.i. 0.89 to 1.03; P = 0.281)) or invasive breast cancer (OR 1.02 (95 per cent c.i. 0.96 to 1.10; P = 0.518))., Conclusion: RSL is rapidly replacing WGL as the preoperative localization technique in breast surgery. This large nationwide registry study found no association between the type of localization technique and the odds of having a reoperation, thus confirming the results of previous prospective cohort studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The goal of this study was to describe the variation in hospital-based diagnostic care activities for patients with symptomatology suspect for breast cancer in The Netherlands. Two cohorts were included: the 'benign' cohort (30,334 women suspected of, but without breast cancer) and the 'malignant' cohort (2236 breast cancer patients). Hospital-based financial data was combined with tumor data (malignant cohort) from The Netherlands Cancer Registry. Patterns within diagnostic pathways were analyzed. Factors influencing the number of visits and number of diagnostic care activities until diagnosis were identified in the malignant cohort with multivariable Cox and Poisson regression models. Compared to patients with benign diagnosis, patients with malignant disease received their diagnosis less frequently in one day, after an equal average number of hospital visits and higher average number of diagnostic activities. Factors increasing the number of diagnostic care activities were the following: lower age and higher cM-and cN-stages. Factors increasing the number of days until (malignant) diagnosis were as follows: higher BIRADS-score, screen-detected and higher cN-and cT-stages. Hospital of diagnosis influenced both number of activities and days to diagnosis. The diagnostic care pathway of patients with malignant disease required more time and diagnostic activities than benign disease and depends on hospital, tumor and patient characteristics.

Background: Previous studies have shown that socioeconomic status (SES) influences breast cancer therapy. However, these studies were performed in countries with unequal access to healthcare. Therefore, the aim of this study is to investigate whether SES also contributes to the likelihood of receiving a certain therapy in the Netherlands, a country with supposedly equal access to healthcare., Materials and Methods: From the Netherlands Cancer Registry, 105,287 patients with newly diagnosed stage I or II breast cancer diagnosed between 2011 and 2018 were selected for analysis. SES was calculated from the average incomes of each postal code, which were divided into 10 deciles. Primary outcome was the effect of SES on the likelihood of undergoing surgery and secondary outcome was the effect of SES on the likelihood of the type of surgery. Both outcomes were corrected for patient, tumor, and hospital characteristics and were expressed as odds ratio (OR) with 95% confidence interval (CI)., Results: SES did not affect the likelihood of a breast cancer patient to undergo surgery (OR 1.00 per 10% stratum). In contrast, increased age and higher tumor stage were the most important factors determining whether patients underwent surgery. Patients with higher SES were less likely to undergo mastectomy (OR 0.98). Additionally, more recently diagnosed patients were less likely to undergo mastectomy (OR 0.93 per year) while patients with higher tumor stage were more likely to undergo mastectomy (OR 3.42)., Conclusion: SES does not affect whether a patient undergoes surgery; however, higher SES increased the likelihood of BCT., (© 2021. The Author(s).)

Background: Regional recurrence (RR), also known as lymph node recurrence, is an endpoint in several trials concerning reducing axillary treatment in cT1-2N0 breast cancer patients. The risk of RR may decrease with each subsequent event-free year, affecting the yield and consequently usefulness of long (er) follow-up. The aim of this study is to determine the risk of RR as a first event within five years after diagnosis in subtypes of breast cancer, conditional to being event-free for one, two, three and four years., Methods: From the Netherlands Cancer Registry, cT1-2N0 breast cancer patients diagnosed from 2005 to 2008 were analyzed. Subgroup analysis was performed for pT1-2N+(sn) patients. RR risk was calculated with Kaplan-Meier analysis. Conditional RR (assuming x event-free years) was determined by selecting patients without an event at x years, and calculating the remaining risk for RR within five years after diagnosis., Results: A total of 18,009 cT1-2N0 (all pN stages) breast cancer patients were included. RR occurred in 1.3% of cT1-2N0 and 1.5% of pT1-2N+(sn) patients. The risk of RR varied between subtypes; it was highest for triple negative tumors and lowest for ER + PR + Her2-and ER + Her2+ tumors. After event-free years, the risk of RR decreased subsequently in both groups and in all subtypes. After two event-free years, the risk of RR was 0.8%., Conclusion: The absolute yield of follow-up to detect RR beyond two years is low; for every 125 event-free patients, one RR can be expected until five years. This suggests that follow-up longer than two years is of limited value for detecting RR in both clinical and research setting., Competing Interests: Declaration of competing interest None of the authors reported have a conflict of interest related to the outcomes of this study., (Copyright © 2020. Published by Elsevier Ltd.)

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.

The tumour microenvironment has been shown to be a valuable source of prognostic information for different cancer types. This holds in particular for triple negative breast cancer (TNBC), a breast cancer subtype for which currently no prognostic biomarkers are established. Although different methods to assess tumour infiltrating lymphocytes (TILs) have been published, it remains unclear which method (marker, region) yields the most optimal prognostic information. In addition, to date, no objective TILs assessment methods are available. For this proof of concept study, a subset of our previously described TNBC cohort (n = 94) was stained for CD3, CD8 and FOXP3 using multiplex immunohistochemistry and subsequently imaged by a multispectral imaging system. Advanced whole-slide image analysis algorithms, including convolutional neural networks (CNN) were used to register unmixed multispectral images and corresponding H&E sections, to segment the different tissue compartments (tumour, stroma) and to detect all individual positive lymphocytes. Densities of positive lymphocytes were analysed in different regions within the tumour and its neighbouring environment and correlated to relapse free survival (RFS) and overall survival (OS). We found that for all TILs markers the presence of a high density of positive cells correlated with an improved survival. None of the TILs markers was superior to the others. The results of TILs assessment in the various regions did not show marked differences between each other. The negative correlation between TILs and survival in our cohort are in line with previous studies. Our results provide directions for optimizing TILs assessment methodology., Competing Interests: Declaration of competing interest Jeroen van der Laak is member of the scientific advisory boards of Philips, the Netherlands and ContextVision, Sweden and receives research funding from Philips, the Netherlands and Sectra, Sweden. Geert Litjens received research funding from Philips Digital Pathology Solutions (Best, the Netherlands) and has a consultancy role for Novartis (Basel, Switzerland). The other authors have no conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol., Methods and Materials: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03)., Results: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients., Conclusions: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Cox Proportional Hazards (CPH) analysis is the standard for survival analysis in oncology. Recently, several machine learning (ML) techniques have been adapted for this task. Although they have shown to yield results at least as good as classical methods, they are often disregarded because of their lack of transparency and little to no explainability, which are key for their adoption in clinical settings. In this paper, we used data from the Netherlands Cancer Registry of 36,658 non-metastatic breast cancer patients to compare the performance of CPH with ML techniques (Random Survival Forests, Survival Support Vector Machines, and Extreme Gradient Boosting [XGB]) in predicting survival using the [Formula: see text]-index. We demonstrated that in our dataset, ML-based models can perform at least as good as the classical CPH regression ([Formula: see text]-index [Formula: see text]), and in the case of XGB even better ([Formula: see text]-index [Formula: see text]). Furthermore, we used Shapley Additive Explanation (SHAP) values to explain the models' predictions. We concluded that the difference in performance can be attributed to XGB's ability to model nonlinearities and complex interactions. We also investigated the impact of specific features on the models' predictions as well as their corresponding insights. Lastly, we showed that explainable ML can generate explicit knowledge of how models make their predictions, which is crucial in increasing the trust and adoption of innovative ML techniques in oncology and healthcare overall.

Background: Observational studies in metastatic breast cancer (MBC) show that long-term overall survival (OS) is associated with limited tumor burden, or oligo-MBC (OMBC). However, a uniform definition of OMBC is lacking. In this real-world nationwide cohort, we aimed to define the optimal OMBC threshold and factors associated with survival in patients with OMBC., Methods: 3535 patients aged younger than 80 years at diagnosis of de novo MBC in the Netherlands between January 2000 and December 2007 were included. Detailed clinical, therapy, and outcome data were collected from medical records of a sample of the patients. Using inverse-sampling-probability weighting, the analysis cohort (n = 3447) was constructed. We assessed OS according to number of metastases at diagnosis to determine the optimal OMBC threshold. Next, we applied Cox regression models with inverse-sampling-probability weighting to study associations with OS and progression-free survival in OMBC. All statistical tests were 2-sided., Results: Compared with more than 5 distant metastases, adjusted hazard ratios for OS (with 95% confidence interval [CI] based on robust standard errors) for 1, 2-3, and 4-5 metastases were 0.70 (95% CI = 0.52 to 0.96), 0.63 (95% CI = 0.45 to 0.89), and 0.91 (95% CI = 0.61 to 1.37), respectively. Ten-year OS estimates for patients with no more than 3 vs more than 3 metastases were 14.9% and 3.4% ( P  <   .001). In multivariable analyses, premenopausal andperimenopausal status, absence of lung metastases, and local therapy of metastases (surgery and/or radiotherapy) added to systemic therapy were statistically significantly associated with better OS and progression-free survival in OMBC, independent of local therapy of the primary tumor., Conclusion: OMBC defined as MBC limited to 1-3 metastases was associated with favorable OS. In OMBC, local therapy of metastases was associated with better OS, particularly if patients were premenopausal or perimenopausal without lung metastases., (© The Author(s) 2021. Published by Oxford University Press.)

Our study was performed to determine the frequency of recall for bilateral breast lesions at screening mammography and compare its outcome with respect to unilateral recall. We included 329 132 screening mammograms (34 889 initial screens and 294 243 subsequent screens) from a Dutch screening mammography program between January 2013 and January 2018. During a 2-year follow-up, we collected radiological data, pathology reports and surgical reports of all recalled women. At bilateral recall, the lesion with the highest Breast Imaging Reporting and Data System score was used as the index lesion when comparing screening mammography characteristics at bilateral vs unilateral recall. A total of 9806 women were recalled at screening (recall rate, 3.0%). Bilateral recall comprised 2.8% (271/9806) of all recalls. Biopsy was more frequently performed after bilateral recall than unilateral recall (54.6% [148/271] vs 44.1% [4201/9535], P < .001), yielding a lower positive predictive value (PPV) of biopsy after bilateral recall (42.6% vs 51.7%, P = .029). The PPV of recall was comparable for both groups (23.2% [63/271] vs 22.8% [2173/9535], P = .85). Invasive cancers after bilateral recall were larger than those diagnosed after unilateral recall (P = .02), but histological subtype, histologic grading, receptor status and proportions of lymph node positive cancers were comparable. Bilateral recall infrequently occurs at screening mammography. Biopsy is more frequently performed following bilateral recall, but the PPV of recall is similar for unilateral and bilateral recall. Invasive cancers of both groups show comparable pathological features except of a larger tumor size after bilateral recall., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Salivary and mammary gland tumors show morphological similarities and share various characteristics, including frequent overexpression of hormone receptors and female preponderance. Although this may suggest a common etiology, it remains unclear whether patients with a salivary gland tumor carry an increased risk of breast cancer (BC). Our purpose was to determine the risk of BC in women diagnosed with salivary gland carcinoma (SGC) or pleomorphic adenoma (SGPA). BC incidence (invasive and in situ) was assessed in two nationwide cohorts: one comprising 1567 women diagnosed with SGC and one with 2083 women with SGPA. BC incidence was compared with general population rates using standardized incidence ratio (SIR). BC risk was assessed according to age at SGC/SGPA diagnosis, follow-up time and (for SGC patients) histological subtype. The mean follow-up was 7.0 years after SGC and 9.9 after SGPA diagnosis. During follow-up, 52 patients with SGC and 74 patients with SGPA developed BC. The median time to BC was 6 years after SGC and 7 after SGPA. The cumulative risk at 10 years of follow-up was 3.1% after SGC and 3.5% after SGPA (95% Confidence Interval (95%CI) 2.1%-4.7% and 2.6%-4.6%, respectively). BC incidence was 1.59 times (95%CI 1.19-2.09) higher in the SGC-cohort than expected based on incidence rates in the general population. SGPA-patients showed a 1.48 times (95%CI 1.16-1.86) higher incidence. Women with SGC or SGPA have a slightly increased risk of BC. The magnitude of risk justifies raising awareness, but is no reason for BC screening., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aims: Histological grade is widely used to guide the management of invasive breast cancer (IBC). Yet, substantial interlaboratory and intralaboratory grading variations exist in daily pathology practice. To create awareness and to facilitate quality improvement, feedback reports, containing case-mix-adjusted laboratory-specific grades benchmarked against other laboratories, were sent to the individual laboratories by 1 March 2018. We studied the effect of these feedback reports on interlaboratory grading variation up till 1 year later., Methods: Overall, 17 102 synoptic pathology reports of IBC resection specimens from 33 laboratories, obtained between 1 March 2017 and 1 March 2019 were retrieved from the Dutch Pathology Registry (PALGA). An overall deviation score (ODS), representing the sum of deviations from the grade-specific overall proportions, was calculated to compare the absolute deviation for all grades at once. Case-mix correction was performed by two multivariable logistic regression analyses, providing laboratory-specific ORs for high-grade versus low-grade IBC., Results: After feedback, the overall range between laboratories decreased by 3.8%, 6.4% and 6.6% for grades I, II and III, respectively. Though the mean ODS remained similar (13.8% vs 13.7%), the maximum ODS decreased from 34.1% to 29.4%. The range of laboratory-specific ORs decreased by 21.9% for grade III versus grades I-II., Conclusions: An encouraging decrease in grading variation of IBC was observed after laboratory-specific feedback. Nevertheless, the overall grading variation remains substantial. In view of the important role of grading in patient management, it is adamant that not only feedback should be provided on a regular basis but also other interventions, such as additional training, are required., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: OSNA is a molecular technique for sentinel lymph node (SN) analysis in breast cancer. Compared to histology, OSNA may yield more (micro)metastases and thereby result in more axillary lymph node dissections or radiotherapy. We investigated whether axillary treatments increase when using OSNA, applying current guidelines for de-escalating axillary management., Methods: All patients treated for cT1-3N0 breast cancer in our hospital between December 2013 and February 2016 were included. In 148 prospectively included patients (January 2015-February 2016), SN's were examined with OSNA. In a retrospective cohort of 123 patients (December 2013-December 2014), SN's were examined with conventional histology. Outcomes were: number of macro and micrometastases, amount of patients receiving axillary dissection or irradiation, number of patients receiving adjuvant systemic therapy. Data were analyzed using Mann-Whitney and Pearson Chi-square test. P < 0.05 was considered statistically significant., Results: 230 SN's from 123 patients were examined with conventional histology. 229 SN's from 148 patients were evaluated with OSNA. Amount of macrometastases was equal between groups (histology 17.9% versus OSNA 16.2%, p = 0.715). We found significantly more micrometastases when using OSNA (histology 11.4% versus OSNA 25.0%, p = 0.004). Total number of axillary lymph node dissections was comparable in both groups (histology 12.2%, OSNA 12.2%, p = 0.993), as well as number of axillary radiations (histology 8.9%, OSNA 11.5%, p = 0.493). Also, the number of patients receiving adjuvant systemic therapy was similar between conventional histology and OSNA (histology 53.7% versus OSNA 58.1%, p = 0.462)., Conclusion: OSNA analysis for SN in breast cancer is a highly sensitive technique, detecting more micrometastases than standard histology. When applying current guidelines, OSNA analysis does not lead to overtreatment with more axillary dissections or irradiation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In 20-25% of patients with biopsy-proven DCIS underestimation occurs. Sentinel lymph node biopsy (SLNB) is offered to patients with biopsy-proven ductal carcinoma in situ (DCIS) and a high risk of occult invasive cancer. However, assessment of high risk is controversial. We aimed to improve selection of patients for SLNB with preoperative breast magnetic resonance imaging (MRI)., Methods: In this prospective observational study, MRI was offered to all subsequent patients with a biopsy-proven DCIS admitted to a large Dutch teaching hospital between April 2012 and March 2017. MRI images were analysed for signs of invasive cancer and the results were compared with the pathologic results after surgical treatment. The diagnostic accuracy of additional MRI in detecting occult invasive cancer was determined., Results: Of 211 patients eligible for additional MRI analysis, 149 underwent breast MRI. The majority (67%) received breast-conserving therapy, and the underestimation rate was 20%. Subsequent to MRI analysis, 20 additional invasive diagnostic procedures were performed. Occult invasive cancer was suspected on MRI in 46 patients (31%) and was confirmed in 18 (12%). In this study, breast MRI had a sensitivity of 67%, a specificity of 77%, and a true negative rate of 91%., Conclusion: Preoperative breast MRI cannot reliably predict the presence of invasive cancer in patients with biopsy proven DCIS. Therefore, it cannot be used to in the selection of patients for a SLNB., Competing Interests: Declaration of competing interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: Better cosmetic outcome after vacuum assisted excision (VAE) compared to surgical excision of benign breast lesions is suggested in previous studies but has never been evaluated with validated outcome measures. In this study, patient reported cosmetic outcome after VAE was evaluated., Methods: Patients who underwent VAE between July 2017 and December 2018 were invited to complete the cosmetic subscale of the Dutch Breast Cancer Treatment Outcome Scale, comparing the treated with the untreated breast. Response mode ranged from 1 (no difference) to 4 (large difference) and cosmetic outcome was calculated as the unweighted mean. Clinical outcomes included: tumor size, number of cores, complications, residual lesions and recurrences., Results: Response rate was 73.4% (47 of 64 patients). Median tumor size was 15 mm (range 5-51 mm) and median number of cores 6.5 (range 1-85), complete excision was confirmed in all but two patients. Mean cosmetic outcome was good (mean score ≤1.75) in 74% of patients and no patients reported a poor cosmetic outcome (mean score >3.25). A hematoma occurred in five patients (one needed aspiration) and a skin rash in one patient, no patients developed an infection or seroma., Conclusion: In this study VAE is safe and effective for tumors up to 5 cm and patient reported cosmetic outcome was good. Patients with benign lesions could benefit from VAE as an alternative for surgical excision., Advances in Knowledge: A formal quantitative measurement of cosmetic outcome after vacuum assisted excision for benign breast lesions was still lacking. This study shows that this cosmetic outcome is overall good in benign lesions up to 5 cm.

Background: To estimate the percentages of advanced-stage breast cancers (BCs) detected during the course of a steady-state screening programme when using different definitions of advanced BC., Methods: Data of women aged 49-74 years, diagnosed with BC in 2006-2015, were selected from the Netherlands Cancer Registry and linked to the screening registry. BCs were classified as screen-detected, interval or non-screened. Three definitions of advanced BC were used for comparison: TNM stage (III-IV), NM stage (N+ and/or M+) and T size (invasive tumour ≥15 mm). Analyses were performed assuming a 10% overdiagnosis rate. In sensitivity analyses, this assumption varied from 0 to 30%., Results: We included 46,734 screen-detected, 17,362 interval and 24,189 non-screened BCs. By TNM stage, 4.9% of screen-detected BCs were advanced, compared with 19.4% and 22.8% of interval and non-screened BCs, respectively (p < 0.001). Applying the other definitions led to higher percentages of advanced BC being detected. Depending on the definition interval, non-screened BCs had a 2-5-times risk of being advanced., Conclusion: Irrespective of the definition, screen-detected BCs were less frequently in the advanced stage. These findings provide evidence of a stage shift to early detection and support the potential of mammographic screening to reduce treatment-related burdens and the mortality associated with BC.

Background: Surgery is increasingly being omitted in older patients with operable breast cancer in the Netherlands. Although omission of surgery can be considered in frail older patients, it may lead to inferior outcomes in non-frail patients. Therefore, the aim of this study was to evaluate the effect of omission of surgery on relative and overall survival in older patients with operable breast cancer., Methods: Patients aged 80 years or older diagnosed with stage I-II hormone receptor-positive breast cancer between 2003 and 2009 were selected from the Netherlands Cancer Registry. An instrumental variable approach was applied to minimize confounding, using hospital variation in rate of primary surgery. Relative and overall survival was compared between patients treated in hospitals with different rates of surgery., Results: Overall, 6464 patients were included. Relative survival was lower for patients treated in hospitals with lower compared with higher surgical rates (90·2 versus 92·4 per cent respectively after 5 years; 71·6 versus 88·2 per cent after 10 years). The relative excess risk for patients treated in hospitals with lower surgical rates was 2·00 (95 per cent c.i. 1·17 to 3·40). Overall survival rates were also lower among patients treated in hospitals with lower compared with higher surgical rates (48·3 versus 51·3 per cent after 5 years; 15·0 versus 19·7 per cent after 10 years respectively; adjusted hazard ratio 1·07, 95 per cent c.i. 1·00 to 1·14)., Conclusion: Omission of surgery is associated with worse relative and overall survival in patients aged 80 years or more with stage I-II hormone receptor-positive breast cancer. Future research should focus on the effect on quality of life and physical functioning., (© 2020 The Authors. British Journal of Surgery published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Purpose: Breast-contour preservation (BCP) is possible for most women treated for early-stage breast cancer. BCP can be defined as primary breast-conserving treatment (BCT), neoadjuvant chemotherapy (NAC) followed by BCT and immediate postmastectomy breast reconstruction (IBR). This study provides insight in current BCP strategies in Denmark and the Netherlands and aims to identify opportunities for improvement within both countries., Methods: A total of 92,881 patients with early-stage breast cancer who were operated in Denmark and the Netherlands between 2012 and 2017 were selected from the Danish Breast Cancer Group and the Dutch National Breast Cancer Audit databases. BCP procedures and predictive factors were analyzed within and between both countries., Results: BCP was achieved in 76.7% (n = 16,355) of the Danish and in 74.5% (n = 53,328) of the Dutch patients. While BCP rate did not change significantly over time in Denmark (p = 0.250), a significant increase in BCP rate from 69.5% in 2012 to 78.5% in 2017 (p < 0.001) was observed in the Netherlands. In both countries, variation in BCP rates between hospitals decreased over time. NAC followed by BCT and postmastectomy IBR was substantially more often used in the Netherlands compared to Denmark, specifically in patients younger than 50 years., Conclusions: In more than 75% of all Danish and Dutch patients, surgically treated for early-stage breast cancer, the breast-contour was preserved. The different use of BCP strategies within Denmark and the Netherlands and the differences observed between hospitals in both countries emphasize the need for more (inter)national consensus on treatment modalities.

Background: Delay in detection of breast cancer may worsen tumour characteristics, with progression of tumour size and a higher risk of metastatic lymph nodes. The purpose of this study was to investigate delayed breast cancer diagnosis after repeated recall for the same mammographic abnormality at screening., Methods: This was a retrospective study performed in two cohorts of women enrolled in a mammography screening programme in the Netherlands. All women aged 50-75 who underwent biennial screening mammography either between January 1, 1997 and December 31, 2006 (cohort 1) or between January 1, 2007 and December 31, 2016 (cohort 2) were included., Results: The cohorts showed no difference in proportions of women with delayed breast cancer diagnosis of at least 2 years (2.2% versus 2.8%, P = 0.29). Most delays were caused by incorrect BI-RADS classifications after recall (74.2%). An increase in mean tumour size was seen when comparing sizes at initial false-negative recall and at diagnosis of breast cancer (P < 0.001)., Conclusions: The proportion of women with a long delay in breast cancer confirmation following repeated recall at screening mammography has not decreased during 20 years of screening. These delays lead to larger tumour size at detection and may negatively influence prognosis.

The DENSE trial has demonstrated that offering an MRI scan to women with very dense glandular breast tissue and normal results on screening mammography reduces the number of interval cancers by 50%. In the women who agreed to undergo an MRI (59%), this reduction was 80% (from 5 per 1000 to 1 per 1000 participants). DENSE will continue in order to answer the only question that is relevant to patients: does additional MRI lead to less invasive treatment and, above all, to a decrease in mortality? Even in the event where additional MRI screening would lead to a decrease in mortality, we still need to have an open discussion on whether investing in additional MRI screening for women with very dense glandular tissue is the most effective way to improve the health of the Dutch female population. Thanks to the great effort of the DENSE research team, such a discussion can be pursued thoroughly, based on facts.

Background: We conducted a prospective cohort study in the Netherlands (RAPCHEM: NCT01279304, BOOG 2010-03) in breast cancer (BC) patients treated with primary systemic therapy (PST), followed by surgery and post-operative radiation therapy (RT) according to a predefined consensus-based study-guideline (SG). The aim of the current analysis is to evaluate adherence to the SG., Methods: From January 2011 to January 2015, patients with cT1-2N1 BC treated in 17 Dutch RT Centres were included. Patients with four or more suspicious nodes at imaging were excluded. SG recommended whole breast RT for patients treated with breast conserving therapy. SG on loco(-regional) RT were defined for three risk groups based on the ypN status: (1) ypN0 (low-risk): RT breast and no RT after mastectomy; (2) ypN1 (intermediate-risk): RT breast or chest wall; (3) ypN2 (high-risk): RT breast or chest wall, including regional lymph nodes., Results: We included 848 patients: 292 in the low-risk group; 374 in the intermediate-risk group; 182 in the high-risk group. Overall, 64% of the patients was treated according to the SG; 11% received less RT than the predefined target volumes and 25% received more extensive RT than according to the SG. The largest variation was seen in the intermediate risk group, where only 54% was treated according to the SG., Conclusion: Substantial deviation from the SG for post-operative RT was observed after PST, especially in patients with an intermediate-risk. Future analyses will evaluate outcome of these patients in relation to risk factors and the actual RT given., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: An overall trend is observed towards de-escalation of axillary surgery in patients with breast cancer. The objective of this study was to evaluate this trend in patients treated with neoadjuvant systemic therapy (NST)., Methods: Patients with cT1-4N0-3 breast cancer treated with NST (2006-2016) were selected from the Netherlands Cancer Registry. Patients were classified by clinical node status (cN) and type of axillary surgery. Uni- and multivariable logistic regression analyses were performed to determine the clinicopathological factors associated with performing ALND in cN+ patients., Results: A total of 12,461 patients treated with NST were identified [5830 cN0 patients (46.8%), 6631 cN+ patients (53.2%)]. In cN0 patients, an overall increase in sentinel lymph node biopsy (SLNB) only (not followed by ALND) was seen from 11% in 2006 to 94% in 2016 (p < 0.001). SLNB performed post-NST increased from 33 to 62% (p < 0.001). In cN+ patients, an overall decrease in ALND was seen from 99% in 2006 to 53% in 2016 (p < 0.001). Age (OR 1.01, CI 1.00-1.02), year of diagnosis (OR 0.47, CI 0.44-0.50), HER2-positive disease (OR 0.62, CI 0.52-0.75), clinical tumor stage (T2 vs. T1 OR 1.32, CI 1.06-1.65, T3 vs. T1 OR 2.04, CI 1.58-2.63, T4 vs. T1 OR 6.37, CI 4.26-9.50), and clinical nodal stage (N3 vs. N1 OR 1.65, CI 1.28-2.12) were correlated with performing ALND in cN+ patients., Conclusions: ALND decreased substantially over the past decade in patients treated with NST. Assessment of long-term prognosis of patients in whom ALND is omitted after NST is urgently needed.

Background Trends in the detection of suspicious microcalcifications at mammography screening and the yield of these lesions after recall are unknown. Purpose To determine trends in recall and outcome of screen-detected microcalcifications during 20 years of mammography screening. Materials and Methods The authors performed a retrospective analysis of a consecutive series of 817 656 screening examinations (January 1997 to January 2017) in a national breast screening program. In 2009-2010 (transition period), screen-film mammography (SFM) was gradually replaced by full-field digital mammography (FFDM). The recalls of suspicious microcalcifications from all radiology reports and pathologic outcome of recalled women with 2-year follow-up were analyzed. Screening outcome in the era of SFM (1997-2008), the transition period (2009-2010), and the era of FFDM (2011-2016) were compared. Trends over time and variations between the SFM and FFDM periods were expressed by using proportions with 95% confidence intervals (CIs). In cases where the analysis based on the CI confirmed clear periods (eg, before and after introduction of FFDM), pre- and postchange outcomes were compared by using χ 2 tests. Results A total of 18 592 women (median age, 59 years; interquartile range, 14 years) were recalled at mammography screening, 3556 of whom had suspicious microcalcifications. The recall rate for microcalcifications increased from 0.1% in 1997-1998 to 0.5% in 2015-2016 ( P < .001). This was temporally associated with the change from SFM to FFDM. The recalls yielding ductal carcinoma in situ (DCIS) increased from 0.3 per 1000 screening examinations with SFM to 1.1 per 1000 screening examinations with FFDM ( P < .001), resulting in a decrease in the positive predictive value for recall for suspicious microcalcifications from 51% to 33% ( P < .001). More than half of all DCIS lesions were high grade (52.6%; 393 of 747). The distribution of DCIS grades was stable during the 20-year screening period ( P = .36). Conclusion The recall rate for suspicious microcalcifications at mammographic screening increased during the past 2 decades, whereas the ductal carcinoma in situ detection rate increased less rapidly, resulting in a lower positive predictive value for recall. © RSNA, 2020.

Accurate, consistent and reproducible grading by pathologists is of key-importance for identification of individual patients with invasive breast cancer (IBC) that will or will not benefit from adjuvant systemic treatment. We studied the laboratory-specific grading variation using nationwide real-life data to create insight and awareness in grading variation. Synoptic pathology reports of all IBC resection-specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch Pathology Registry (PALGA). Absolute differences in laboratory-proportions of Grades I-III were compared to the national reference. Multivariable logistic regression provided laboratory-specific odds ratios (ORs) for high- vs. low-grade IBC. 33,792 IBC pathology reports of 33,043 patients from 39 laboratories were included, of which 28.1% were reported as Grade I (range between laboratories 16.3-43.3%), 47.6% as Grade II (38.4-57.8%), and 24.3% as Grade III (15.5-34.3%). Based on national guidelines, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. After case-mix correction, 20 laboratories (51.3%) showed a significantly deviant OR. Significant grading differences were also observed among pathologists within laboratories. In this cohort of 33,043 breast cancer patients, we observed substantial inter- and intra-laboratory variation in histologic grading. It can be anticipated that this has influenced outcome including exposure to unnecessary toxicity, since choice of adjuvant chemotherapy was dependent on grade in nearly a third of patients. Better standardization and training seems warranted., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objective: We aimed to compare frailty status between patients with head and neck cancer (HNC) and other solid malignancies., Methods: Data collection was prospective, and the following were compared between cohorts at baseline: patient and tumour characteristics, Charlson Comorbidity Index (CCI), Groningen Frailty Indicator (GFI), Mini Mental State Examination (MMSE), Activities of Daily Living (ADLs), Instrumental ADLs (IADLs), Timed Up and Go (TUG) and Quality of Life (QoL). Univariate and multivariate logistic regression analyses were performed, and odds ratios (ORs) with their 95% confidence intervals (95% CIs) were estimated., Results: In total, 242 patients with HNC and 180 with other oncology diagnoses were enrolled, of whom 32.6% and 21.8% were frail according to the GFI respectively. Comorbidity scores were not significantly different between the cohorts (7.4% vs. 13.1%; OR 0.54; 95% CI 0.28-1.02). In the univariate analysis, the GFI was significantly worse in the HNC cohort (OR 1.74; 95% CI 1.11-2.71). However, in the multivariate analysis, the MMSE, TUG and global QoL were significantly worse in the HNC cohort, with ORs of 20.03 (95% CI 2.44-164.31), 11.56 (95% CI 1.86-71.68) and 0.98 (95% CI 0.97-1.00) respectively., Conclusion: Patients with HNC appear to be frailer than patients with other solid malignancies despite comparable levels of comorbidity., (© 2019 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)