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Investigators of registry-based studies report improved survival for breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer. As these studies did not present long-term overall and breast cancer-specific survival, the effect of breast-conserving surgery plus radiotherapy might be overestimated. In this study, we aimed to evaluate 10 year overall and breast cancer-specific survival after breast-conserving surgery plus radiotherapy compared with mastectomy in Dutch women with early breast cancer. In this population-based study, we selected all women from the Netherlands Cancer Registry diagnosed with primary, invasive, stage T1–2, N0–1, M0 breast cancer between Jan 1, 2000, and Dec 31, 2004, given either breast-conserving surgery plus radiotherapy or mastectomy, irrespective of axillary staging or dissection or use of adjuvant systemic therapy. Primary outcomes were 10 year overall survival in the entire cohort and breast cancer-specific survival in a representative subcohort of patients diagnosed in 2003 with characteristics similar to the entire cohort. We estimated breast cancer-specific survival by calculating distant metastasis-free and relative survival for every tumour and nodal category. We did multivariable Cox proportional hazard analysis to estimate hazard ratios (HRs) for overall and distant metastasis-free survival. We estimated relative survival by calculating excess mortality ratios using life tables of the general population. We did multiple imputation to account for missing data. Of the 37 207 patients included in this study, 21 734 (58%) received breast-conserving surgery plus radiotherapy and 15 473 (42%) received mastectomy. The 2003 representative subcohort consisted of 7552 (20%) patients, of whom 4647 (62%) received breast-conserving surgery plus radiotherapy and 2905 (38%) received mastectomy. For both unadjusted and adjusted analysis accounting for various confounding factors, breast-conserving surgery plus radiotherapy was significantly associated with improved 10 year overall survival in the whole cohort overall compared with mastectomy (HR 0·51 [95% CI 0·49–0·53]; p<0·0001; adjusted HR 0·81 [0·78–0·85]; p<0·0001), and this improvement remained significant for all subgroups of different T and N stages of breast cancer. After adjustment for confounding variables, breast-conserving surgery plus radiotherapy did not significantly improve 10 year distant metastasis-free survival in the 2003 cohort overall compared with mastectomy (adjusted HR 0·88 [0·77–1·01]; p=0·07), but did in the T1N0 subgroup (adjusted 0·74 [0·58–0·94]; p=0·014). Breast-conserving surgery plus radiotherapy did significantly improve 10 year relative survival in the 2003 cohort overall (adjusted 0·76 [0·64–0·91]; p=0·003) and in the T1N0 subgroup (adjusted 0·60 [0·42–0·85]; p=0·004) compared with mastectomy. Adjusting for confounding variables, breast-conserving surgery plus radiotherapy showed improved 10 year overall and relative survival compared with mastectomy in early breast cancer, but 10 year distant metastasis-free survival was improved with breast-conserving surgery plus radiotherapy compared with mastectomy in the T1N0 subgroup only, indicating a possible role of confounding by severity. These results suggest that breast-conserving surgery plus radiotherapy is at least equivalent to mastectomy with respect to overall survival and may influence treatment decision making for patients with early breast cancer. None.

Background Pathological complete response (pCR) is the ultimate response in breast cancer patients treated with neoadjuvant chemotherapy (NCT). It might be a surrogate outcome for disease-free survival (DFS) and overall survival (OS). We studied the effect of clinical tumor stage (cT-stage) on tumor pCR and the effect of pCR per cT-stage on 5-year OS and DFS. Methods Using the Netherlands Cancer Registry, all primary invasive breast cancer patients treated with NCT from 2005 until 2008 were identified. Univariable logistic regression analysis was performed to evaluate the effect of cT-stage on pCR, stepwise logistic regression analysis to correct for potential confounders and Kaplan–Meier survival analyses to calculate OS and DFS after five years. Results In 2366 patients, overall pCR rate was 21%. For cT1, cT2, cT3, and cT4, pCR rates were 31, 22, 18, and 17%, respectively. Lower cT-stage (cT1-2 vs cT3-4) was a significant independent predictor of higher pCR rate ( p  < 0.001, OR 3.15). Furthermore, positive HER2 status ( p  < 0.001, OR 2.30), negative estrogen receptor status ( p  = 0.062, OR 1.69), and negative progesterone receptor status ( p  = 0.008, OR 2.27) were independent predictors of pCR. OS and DFS were up to 20% higher in patients with cT2-4 tumors with pCR versus patients without pCR. DFS was also higher for cT1 tumors with pCR. Conclusions The most important predictor of pCR in breast cancer patients is cT-stage: lower cT-stages have significantly higher pCR rates than higher cT-stages. Patients with cT2-4 tumors achieving pCR have higher OS and DFS compared to patients not achieving pCR.

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.

Oncological care was largely derailed due to the reprioritisation of health care services to handle the initial surge of COVID-19 patients adequately. Cancer screening programmes were no exception in this reprioritisation. They were temporarily halted in the Netherlands (1) to alleviate the pressure on health care services overwhelmed by the upsurge of COVID-19 patients, (2) to reallocate staff and personal protective equipment to support critical COVID-19 care, and (3) to mitigate the spread of COVID-19. Utilising data from the Netherlands Cancer Registry on provisional cancer diagnoses between 6 January 2020 and 4 October 2020, we assessed the impact of the temporary halt of national population screening programmes on the diagnosis of breast and colorectal cancer in the Netherlands. A dynamic harmonic regression model with ARIMA error components was applied to assess the observed versus expected number of cancer diagnoses per calendar week. Fewer diagnoses of breast and colorectal cancer were objectified amid the early stages of the initial COVID-19 outbreak in the Netherlands. This effect was most pronounced among the age groups eligible for cancer screening programmes, especially in breast cancer (age group 50–74 years). Encouragingly enough, the observed number of diagnoses ultimately reached and virtually remained at the level of the expected values. This finding, which emerged earlier in age groups not invited for cancer screening programmes, comes on account of the decreased demand for critical COVID-19 care since early April 2020, which, in turn, paved the way forward to resume screening programmes and a broad range of non-critical health care services, albeit with limited operating and workforce capacity. Collectively, transient changes in health-seeking behaviour, referral practices, and cancer screening programmes amid the early stages of the initial COVID-19 epidemic in the Netherlands conjointly acted as an accelerant for fewer breast and colorectal cancer diagnoses in age groups eligible for cancer screening programmes. Forthcoming research is warranted to assess whether the decreased diagnostic scrutiny of cancer during the COVID-19 pandemic resulted in stage migration and altered clinical management, as well as poorer outcomes.

PurposeTo extend the functionality of the existing INFLUENCE nomogram for locoregional recurrence (LRR) of breast cancer toward the prediction of secondary primary tumors (SP) and distant metastases (DM) using updated follow-up data and the best suitable statistical approaches.MethodsData on women diagnosed with non-metastatic invasive breast cancer were derived from the Netherlands Cancer Registry (n = 13,494). To provide flexible time-dependent individual risk predictions for LRR, SP, and DM, three statistical approaches were assessed; a Cox proportional hazard approach (COX), a parametric spline approach (PAR), and a random survival forest (RSF). These approaches were evaluated on their discrimination using the Area Under the Curve (AUC) statistic and on calibration using the Integrated Calibration Index (ICI). To correct for optimism, the performance measures were assessed by drawing 200 bootstrap samples.ResultsAge, tumor grade, pT, pN, multifocality, type of surgery, hormonal receptor status, HER2-status, and adjuvant therapy were included as predictors. While all three approaches showed adequate calibration, the RSF approach offers the best optimism-corrected 5-year AUC for LRR (0.75, 95%CI: 0.74–0.76) and SP (0.67, 95%CI: 0.65–0.68). For the prediction of DM, all three approaches showed equivalent discrimination (5-year AUC: 0.77–0.78), while COX seems to have an advantage concerning calibration (ICI < 0.01). Finally, an online calculator of INFLUENCE 2.0 was created.ConclusionsINFLUENCE 2.0 is a flexible model to predict time-dependent individual risks of LRR, SP and DM at a 5-year scale; it can support clinical decision-making regarding personalized follow-up strategies for curatively treated non-metastatic breast cancer patients.

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 Radiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort. Methods The cohort comprised all women diagnosed with DCIS in the Netherlands during 1989–2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models. Results The 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9–32.6) after BCS compared to 18.2% (95% CI 16.3–20.3) following BCS  +  RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR) age < 50 3.2 (95% CI 1.6–6.6); HR age ≥ 50 3.6 (95% CI 2.6–4.8) and for iIBC: HR age<50 2.1 (95% CI 1.4–3.2); HR age ≥ 50 4.3 (95% CI 3.0–6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HR age < 50 0.7 (95% CI 0.3–1.5); HR age ≥ 50 0.7 (95% CI 0.4–1.3) and for iIBC: HR age < 50 0.6 (95% CI 0.4–0.9); HR age ≥ 50 1.2 (95% CI 0.9–1.6)). Conclusion RT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.

ObjectivesThroughout Europe, many countries offer population-based cancer screening programmes (CSPs). In the Netherlands, two implemented CSPs are targeting people of 50 years and older, aiming at breast cancer (BC) and colorectal cancer (CRC). In order for a CSP to be (cost-)effective, high participation rates and outreach to the populations at risk are essential. People living in highly urbanised areas and big cities are known to participate less in CSPs. The aim of this study was to gain further insight into the participation patterns of a screening-eligible population of 50 years and over, living in a highly urbanised region, over a longer time period.DesignA retrospective observational study.SettingParticipation data of the regional screening organisation, linked to the cancer incidence data derived from the Netherlands Cancer Registry, concerning the city of The Hague, between 2005 and 2019. Attendance groups were defined as attenders (attending >50% of the invitations) and non-attenders (attending ≤50% of the invitations), and were mutually compared.ResultsThe databases contained 106 377 unique individuals on the BC screening programme (SP) and 73 669 on the CRC-SP. Non-attendance at both CSPs was associated with living in a lower socioeconomic status (SES) neighbourhood and as a counter effect, also associated with a more unfavourable, relatively late-stage, tumour diagnosis. When combining the results of the two CSPs, our results imply high screening adherence over time. Women who did not participate in both CSPs were older, and more often lived in neighbourhoods with a lower SES score.ConclusionsSince low screening uptake is one of the factors that contribute to increasing inequalities in cancer survival, future outreach strategies should be focused on engaging specific non-attending subgroups.

Background Between 2003 and 2010 digital mammography (DM) gradually replaced screen-film mammography (SFM) in the Dutch breast cancer screening programme (BCSP). Previous studies showed increases in detection rate (DR) after the transition to DM. However, national interval cancer rates (ICR) have not yet been reported. Methods We assessed programme sensitivity and specificity during the transition period to DM, analysing nationwide data on screen-detected and interval cancers. Data of 7.3 million screens in women aged 49–74, between 2004 and 2011, were linked to the Netherlands Cancer Registry to obtain data on interval cancers. Age-adjusted DRs, ICRs and recall rates (RR) per 1000 screens and programme sensitivity and specificity were calculated by year, age and screening modality. Results 41,662 screen-detected and 16,160 interval cancers were analysed. The DR significantly increased from 5.13 (95% confidence interval (CI):5.00–5.30) in 2004 to 6.34 (95% CI:6.15–6.47) in 2011, for both in situ (2004:0.73;2011:1.24) and invasive cancers (2004:4.42;2011:5.07), whereas the ICR remained stable (2004: 2.16 (95% CI2.06–2.25);2011: 2.13 (95% CI:2.04–2.22)). The RR changed significantly from 14.0 to 21.4. Programme sensitivity significantly increased, mainly between ages 49–59, from 70.0% (95% CI:68.9–71.2) to 74.4% (95% CI:73.5–75.4) whereas specificity slightly declined (2004:99.1% (95% CI:99.09–99.13);2011:98.5% (95% CI:98.45–98.50)). The overall DR was significantly higher for DM than for SFM (6.24;5.36) as was programme sensitivity (73.6%;70.1%), the ICR was similar (2.19;2.20) and specificity was significantly lower for DM (98.5%;98.9%). Conclusions During the transition from SFM to DM, there was a significant rise in DR and a stable ICR, leading to increased programme sensitivity. Although the recall rate increased, programme specificity remained high compared to other countries. These findings indicate that the performance of DM in a nationwide screening programme is not inferior to, and may be even better, than that of SFM.

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.