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

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

Background The growing volume of health data provides new opportunities for medical research. By using existing registries, large populations can be studied over a long period of time. Patient-level linkage of registries leads to even more detailed and extended information per patient, but brings challenges regarding responsibilities, privacy and security, and quality of data linkage. In this paper we describe how we dealt with these challenges when creating the Primary Secondary Cancer Care Registry (PSCCR)- Breast Cancer. Methods The PSCCR – Breast Cancer was created by linking two existing registries containing data on 1) diagnosis, tumour and treatment characteristics of all Dutch breast cancer patients (NCR), and 2) consultations and diagnoses from primary care electronic health records of about 10% of Dutch GP practices (Nivel-PCD). The existing registry governance structures and privacy regulations were incorporated in those of the new registry. Privacy and security risks were reassessed. Data were restricted to females and linked using postal code and date of birth. The breast cancer diagnosis was verified in both registries and for a subsample of 44 patients with the GP as well. Results A collaboration agreement was signed in which the organisations retained data responsibility and accountability for ‘their’ registry. A Trusted Third Party performed the record linkage. Ten percent of the patients with breast cancer could be linked to the primary care registry, as was expected based on the coverage of Nivel-PCD, and finally 7 % could be included. The breast cancer diagnosis was verified by the GP in 42 of the 44 patients. Conclusions We developed and validated a procedure for patient-level linkage of health data registries without a unique identifier, while preserving the integrity and privacy of the original registries. The method described may help researchers wishing to link existing health data registries.

In utero exposure to diethylstilbestrol (DES) is associated with increased risk of clear cell adenocarcinoma (CCAC) of the vagina or cervix. It is not clear whether these risks remain increased at older ages, and if the risks of other cancer sites, including breast cancer, are increased. This nationwide cohort study included 12,249 DES-exposed women and 2,070 unexposed sisters. Hormone-related risk factors and medical history were assessed through questionnaires, and cancer incidence through linkages with nationwide registries. Comparison with general population rates showed no difference in overall cancer risk (SIR = 0.98, 95%CI 0.93–1.04) or breast cancer risk (SIR = 1.03, 95%CI 0.96–1.11) for DES-exposed women. The rate of vaginal cancer was strongly increased for DES-exposed women (SIR = 10.5, 95%CI 5.72–17.6) and was increased in all age categories, including age 60–69 years (SIR = 8.3, 95%CI 1.00-29.9). Risks of both CCAC (SIR = 49.1, 95%CI 21.2–96.8) and squamous cell carcinoma (SCC; SIR = 5.86, 95%CI 2.15–12.8) of the vagina were significantly elevated. When comparing DES-exposed women with DES-unexposed sisters, overall cancer risk and risk of breast cancer were similar (HR = 0.93, 95%CI 0.78–1.11 and HR = 0.97, 95%CI 0.76–1.23, respectively). Apart from the established increased risk of vaginal cancer, women exposed to DES in utero do not seem to be at increased risk of cancer, including breast cancer. The risk of vaginal cancer remains increased also for women in their fifties/sixties. Moreover, the increased risk of vaginal cancer was seen for both subtypes CCAC and SCC. Screening for vaginal cancer up to higher ages than currently recommended (< 60 years) should be considered.

Purpose Insights into the severity of co-existing symptoms can help in identifying breast cancer survivors in need of symptom management. We aimed to identify subgroups of breast cancer survivors based on patterns of symptom severity, and characteristics associated with these subgroups. Methods We selected surgically treated stage I–III breast cancer survivors 1–5 years post-diagnosis from the Netherlands Cancer Registry ( N  = 876). We assessed experienced severity of fatigue , nausea , pain , dyspnea , insomnia , appetite , constipation , diarrhea , and emotional and cognitive symptoms through the EORTC-QLQ-C30 Quality of Life Questionnaire on a scale of 0–100. We determined subgroups of survivors using latent class cluster analyses (LCA) based on severity of co-existing symptoms and compared their mean severity to the age-matched female reference population to interpret clinical relevance. We assessed subgroup characteristics by multinomial logistic regression analyses. Results From 404 respondents (46%), three subgroups of survivors with distinct symptom severity were identified: low severity ( n  = 116, 28.7%), intermediate severity ( n  = 224, 55.4%), and high severity ( n  = 59, 14.6%). The low subgroup reported lower symptom severity than the general population; the intermediate subgroup reported a similar symptom severity, although scores for fatigue , insomnia , and cognitive symptoms were worse (small-medium clinical relevance). The high subgroup had worse symptom severity (medium-large clinical relevance). Compared to the intermediate subgroup, one (RRR: 2.75; CI: 1.22–6.19; p  = 0.015) or more (RRR: 9.19; CI: 3.70–22.8; p  =  < 0.001) comorbidities were significantly associated with the high subgroup. We found no associated treatment characteristics. Conclusion We identified distinct subgroups of breast cancer survivors based on symptom severity, underlining the relevance of further exploring personalized follow-up strategies.

IntroductionCardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Some breast cancer treatments including anthracyclines, trastuzumab and radiotherapy can increase the risk of CVD, especially for patients with pre-existing CVD risk factors. Early identification of patients at increased CVD risk may allow switching to less cardiotoxic treatments, active surveillance or treatment of CVD risk factors. One of the strongest independent CVD risk factors is the presence and extent of coronary artery calcifications (CAC). In clinical practice, CAC are generally quantified on ECG-triggered cardiac CT scans. Patients with breast cancer treated with radiotherapy routinely undergo radiotherapy planning CT scans of the chest, and those scans could provide the opportunity to routinely assess CAC before a potentially cardiotoxic treatment. The Bragatston study aims to investigate the association between calcifications in the coronary arteries, aorta and heart valves (hereinafter called ‘cardiovascular calcifications’) measured automatically on planning CT scans of patients with breast cancer and CVD risk.Methods and analysisIn a first step, we will optimise and validate a deep learning algorithm for automated quantification of cardiovascular calcifications on planning CT scans of patients with breast cancer. Then, in a multicentre cohort study (University Medical Center Utrecht, Utrecht, Erasmus MC Cancer Institute, Rotterdam and Radboudumc, Nijmegen, The Netherlands), the association between cardiovascular calcifications measured on planning CT scans of patients with breast cancer (n≈16 000) and incident (non-)fatal CVD events will be evaluated. To assess the added predictive value of these calcifications over traditional CVD risk factors and treatment characteristics, a case-cohort analysis will be performed among all cohort members diagnosed with a CVD event during follow-up (n≈200) and a random sample of the baseline cohort (n≈600).Ethics and disseminationThe Institutional Review Boards of the participating hospitals decided that the Medical Research Involving Human Subjects Act does not apply. Findings will be published in peer-reviewed journals and presented at conferences.Trial registration number NCT03206333.

Objective We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero. Methods A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population. Results A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer. Conclusions Except for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently.

Transgenerational effects of diethylstilbestrol (DES) have been reported in animals, but effects in human beings are unknown. Alerted by two case reports, we aimed to establish the risk of hypospadias in the sons of women who were exposed to DES in utero. We did a cohort study of all sons of a Dutch cohort of 16 284 women with a diagnosis of fertility problems. We used a mailed questionnaire assessing late effects of fertility treatment to identify boys with hypospadias. We compared the prevalence rate of hypospadias between boys with and without maternal DES exposure in utero. 16 284 mothers (response rate 67%) reported 8934 sons. The mothers of 205 boys reported DES exposure in utero. Four of these children were reported to have hypospadias. In the remaining 8729 children, only eight cases of hypospadias were reported (prevalence ratio 21·3 [95% CI 6·5–70·1]). All cases of hypospadias were medically confirmed. Maternal age or fertility treatment did not affect the risk of hypospadias. Children conceived after assisted reproductive techniques such as in-vitro fertilisation were not at increased risk of hypospadias compared with children conceived naturally (1·8, 0·6–5·7). Our findings suggest an increased risk of hypospadias in the sons of women exposed to DES in utero. Although the absolute risk of this anomaly is small, this transgenerational effect of DES warrants additional studies.

To the Editor: Exposure to diethylstilbestrol (DES) in utero is related to an increased risk of clear-cell adenocarcinoma of the vagina and cervix at a young age. 1 However, the long-term risk of cancer in the daughters of women given DES during pregnancy (DES daughters) is still unknown. To date, only one study has examined the risk of cancer in adult DES daughters, and no increased risks were found in that study, except for an increased risk of clear-cell adenocarcinoma of the vagina and cervix. 2 We analyzed data from a questionnaire mailed to 13,350 DES daughters registered at the Netherlands DES . . .