The effectiveness of personalised surveillance and aftercare in breast cancer follow-up: a systematic review.

PURPOSE: Breast cancer follow-up (surveillance and aftercare) varies from one-size-fits-all to more personalised approaches. A systematic review was performed to get insight in existing evidence on (cost-)effectiveness of personalised follow-up. METHODS: PubMed, Scopus and Cochrane were searched between 01-01-2010 and 10-10-2022 (review registered in PROSPERO:CRD42022375770). The inclusion population comprised nonmetastatic breast cancer patients ≥ 18 years, after completing curative treatment. All intervention-control studies studying personalised surveillance and/or aftercare designed for use during the entire follow-up period were included. All review processes including risk of bias assessment were performed by two reviewers. Characteristics of included studies were described. RESULTS: Overall, 3708 publications were identified, 64 full-text publications were read and 16 were included for data extraction. One study evaluated personalised surveillance. Various personalised aftercare interventions and outcomes were studied. Most common elements included in personalised aftercare plans were treatment summaries (75%), follow-up guidelines (56%), lists of available supportive care resources (38%) and PROs (25%). Control conditions mostly comprised usual care. Four out of seven (57%) studies reported improvements in quality of life following personalisation. Six studies (38%) found no personalisation effect, for multiple outcomes assessed (e.g. distress, satisfaction). One (6.3%) study was judged as low, four (25%) as high risk of bias and 11 (68.8%) as with concerns. CONCLUSION: The included studies varied in interventions, measurement instruments and outcomes, making it impossible to draw conclusions on the effectiveness of personalised follow-up. There is a need for a definition of both personalised surveillance and aftercare, whereafter outcomes can be measured according to uniform standards.

Inequalities in the omission of axillary dissection in sentinel lymph node positive patients in the Netherlands: Innovative hospitals are early adopters of a de-escalating approach.

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.

Routine and interval detection of locoregional breast cancer recurrences and risk of subsequent distant metastasis.

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.

Trends of Axillary Treatment in Sentinel Node-Positive Breast Cancer Patients Undergoing Mastectomy.

BACKGROUND: The ACOSOG-Z0011- and the AMAROS-trial obviated the need for axillary surgery in most sentinel node-positive (SLN+) breast cancer patients undergoing breast-conserving surgery (BCS). Data for patients who undergo mastectomy is scarce. The purpose of this study was to investigate patterns of axillary treatment in SLN+ patients treated by mastectomy in the years after the publication of landmark studies regarding axillary treatment in SLN+ breast cancer patients undergoing BCS. METHODS: This was a population-based study in cT1-3N0M0 breast cancer patients treated by mastectomy and staged as SLN+ between 2009 and 2018. The performance of an axillary lymph node dissection (ALND) and/or administration of postmastectomy radiotherapy (PMRT) were primary outcomes and were studied over time. RESULTS: The study included 10,633 patients. The frequency of ALND performance decreased from 78% in 2009 to 10% in 2018, whereas PMRT increased from 4 to 49% (P < 0.001). In ≥N1a patients, ALND performance decreased from 93 to 20%, whereas PMRT increased to 70% (P < 0.001). In N1mi and N0itc patients, ALND was abandoned during the study period, whereas PMRT increased to 38% and 13% respectively (P < 0.001), respectively. Age, tumor subtype, N-stage, and hospital type affected the likelihood that patients underwent ALND. CONCLUSIONS: In this study in SLN+ breast cancer patients undergoing mastectomy, use of ALND decreased drastically over time. By the end of 2018 most ≥N1a patients received PMRT as the only adjuvant axillary treatment, whereas the majority of N1mi and N0itc patients received no additional treatment.

Associations between treatments, comorbidities and multidimensional aspects of quality of life among patients with advanced cancer in the Netherlands-a 2017-2020 multicentre cross-sectional study.

OBJECTIVE: To investigate associations between quality of life (QoL) and 1) immunotherapy and other cancer treatments received three months before QoL measurements, and 2) the comorbidities at the time of completion or in the year prior to QoL measurements, among patients with advanced cancer. METHODS: A cross-sectional study is conducted on patients with advanced cancer in the Netherlands. The data come from the baseline wave of the 2017-2020 eQuiPe study. Participants were surveyed via questionnaires (including EORTC QLQ-C30). Using multivariable linear and logistic regression models, we explored statistical associations between QoL components and immunotherapy and other cancer treatments as well as pre-existing comorbidities while adjusting for age, sex, socio-economic status. RESULTS: Of 1088 participants with median age 67 years, 51% were men. Immunotherapy was not associated with global QoL but was associated with reduced appetite loss (odds ratio (OR) = 0.6, 95%CI = [0.3,0.9]). Reduced global QoL was associated with chemotherapy (adjusted mean difference (ß) = - 4.7, 95% CI [- 8.5,- 0.8]), back pain (ß = - 7.4, 95% CI [- 11.0,- 3.8]), depression (ß = - 13.8, 95% CI [- 21.5,- 6.2]), thyroid diseases (ß = - 8.9, 95% CI [- 14.0,- 3.8]) and diabetes (ß = - 4.5, 95% CI [- 8.9,- 0.5]). Chemotherapy was associated with lower physical (OR = 2.4, 95% CI [1.5,3.9]) and role (OR = 1.8, 95% CI [1.2,2.7]) functioning, and higher pain (OR = 1.9, 95% CI [1.3,2.9]) and fatigue (OR = 1.6, 95% CI [1.1,2.4]). CONCLUSION: Our study identified associations between specific cancer treatments, lower QoL and more symptoms. Monitoring symptoms may improve QoL of patients with advanced cancer. Producing more evidence from real life data would help physicians in better identifying patients who require additional supportive care.

Comprehensive trends in incidence, treatment, survival and mortality of first primary invasive breast cancer stratified by age, stage and receptor subtype in the Netherlands between 1989 and 2017.

Our study aimed to provide a comprehensive overview of trends in incidence, survival, mortality and treatment of first primary invasive breast cancer (BC), according to age, stage and receptor subtype in the Netherlands between 1989 and 2017. Data from all women diagnosed with first primary stage I to IV BC (N = 320 249) were obtained from the Netherlands Cancer Registry. BC mortality and general population data were retrieved from Statistics Netherlands. Age-standardised incidence and mortality rates were calculated with annual percentage change (APC) and average annual percentage change (AAPC) statistics. The relative survival (RS) was used as estimator for disease-specific survival. The BC incidence for all BC patients combined significantly increased until 2013 from 126 to 158 per 100 000 person-years, after which a declining trend was observed. Surgery became less extensive, but (neo-)adjuvant systemic treatments and their combinations were given more frequently. The RS improved for all age groups and for most stages and receptor subtypes, but remained stable for all subtypes since 2012 to 2013 and since 2000 to 2009 for Stage IV BC at 15 years of follow-up. Overall, the 5- and 10-year RS increased from 76.8% (95% confidence interval [CI]: 76.1, 77.4) and 55.9% (95% CI: 54.7, 57.1) in 1989 to 1999 to 91.0% (95% CI: 90.5, 91.5) and 82.9% (95% CI: 82.2, 83.5), respectively, in 2010 to 2016. BC mortality improved regardless of age and overall decreased from 57 to 35 per 100 000 person-years between 1989 and 2017. In conclusion, the BC incidence in the Netherlands has steadily increased since 1989, but the latest trends show promising declines. Survival improved markedly for most patients and the mortality decreased regardless of age.

Improved risk estimation of locoregional recurrence, secondary contralateral tumors and distant metastases in early breast cancer: the INFLUENCE 2.0 model.

PURPOSE: To 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. METHODS: Data 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. RESULTS: Age, 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. CONCLUSIONS: INFLUENCE 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.

Association between initiation of adjuvant chemotherapy beyond 30 days after surgery and overall survival among patients with triple-negative breast cancer.

Delayed time to chemotherapy (TTC) is associated with decreased outcomes of breast cancer patients. Recently, studies suggested that the association might be subtype-dependent and that TTC within 30 days should be warranted in patients with triple-negative breast cancer (TNBC). The aim of the current study is to determine if TTC beyond 30 days is associated with reduced 10-year overall survival in TNBC patients. We identified all TNBC patients diagnosed between 2006 and 2014 who received adjuvant chemotherapy in the Netherlands. We distinguished between breast-conserving surgery (BCS) vs. mastectomy given the difference in preoperative characteristics and outcomes. The association was estimated with hazard ratios (HRs) using propensity-score matched Cox proportional hazard analyses. In total, 3,016 patients were included. In matched patients who underwent BCS (n = 904), 10-year overall survival was favorable for patients with TTC within 30 days (84.4% vs. 76.9%, p = 0.001). Patients with TTC beyond 30 days were more likely than those with TTC within 30 days to die within 10 years after surgery (HR 1.69 (95% CI 1.22-2.34), p = 0.002). In matched patients who underwent mastectomy (n = 1,568), there was no difference in 10 years overall survival between those with TTC within or beyond 30 days (74.5% vs. 74.7%, p = 0.716), nor an increased risk of death for those with TTC beyond 30 days (HR 1.04 (95% CI 0.84-1.28), p = 0.716). Initiation of adjuvant chemotherapy beyond 30 days is associated with decreased 10 years overall survival in TNBC patients who underwent BCS. Therefore, timelier initiation of chemotherapy in TNBC patients undergoing BCS seems warranted.

Quantifying the Mitigating Effects of Whole-Breast Radiotherapy and Systemic Treatments on Regional Recurrence Incidence Among Breast Cancer Patients.

BACKGROUND: Despite the potential for residual lymph node metastases after a negative or positive sentinel lymph node biopsy (SLNB), breast cancer patients rarely experience regional recurrences (RRs). This study aimed to quantify the effects of nonsurgical treatments on RR incidence among SLNB-negative (SLNB N0) breast cancer patients. METHODS: All primary SLNB N0-staged breast cancer patients with a diagnosis between 2005 and 2008 and 5-year follow-up data on recurrences were selected from the Netherlands Cancer Registry. The cumulative incidence function (CIF) for RR was calculated as the first event at 5 years, taking into account any other first-event (local or distant recurrence, contralateral breast cancer, or death) as competing risk. Cox regression analysis was used to model the cause-specific hazard of RR developing as the first event to quantify the effect of adjuvant systemic therapy and whole-breast radiotherapy (RT) on RR incidence at 5 years. RESULTS: The study included 13,512 patients. Of these patients, 162 experienced an RR. The CIF of RR at 5 years was 1.3% (95% confidence interval [CI], 1.1-1.5%), whereas the CIFs for death and other events were 4.4% and 9.5%, respectively. Cox regression analysis showed hazard ratios (HRs) of 0.46 (95% CI 0.33-0.64), 0.31 (95% CI 0.18-0.55), and 0.40 (95% CI 0.24-0.67) respectively for patients treated by RT as a routine part of breast-conserving therapy (BCT), chemotherapy, and hormonal therapy. CONCLUSION: RT as routine part of BCT, chemotherapy, and hormonal therapy independently exerted a mitigating effect on the risk for the development of RR. The three methods at least halved the risk.

Ten-year recurrence rates for breast cancer subtypes in the Netherlands: A large population-based study.

Here we report for the first time the relation between breast cancer subtypes and 10-year recurrence rates and mortality in the Netherlands. All operated women diagnosed with invasive non-metastatic breast cancer in 2005 in the Netherlands were included. Patients were classified into breast cancer subtypes according to ER, PR, HER2 status and grade: luminal A, luminal B, HER2 positive and triple negative. Percentages and hazards of recurrence were compared among subtypes. Adjusted 10-year overall (OS) and recurrence-free survival (RFS) were calculated using multivariable Cox regression. Of 8,062 patients, 4,482 (56%) were luminal A, 2,090 (26%) luminal B, 504 (6%) HER2 positive and 986 (12%) triple negative. Local recurrences (7.5%) and distant metastases (25.6%) occurred most often in HER2 positive disease and the least often in luminal A (3.7% and 9.5%, respectively). Regional recurrences were most often diagnosed in triple negative disease (5.2%), and the least often in luminal A (1.7%). HER2 positive and triple negative subtypes had the highest recurrence rates in the second year, while luminal A and B showed a more continuous pattern over time, with lobular tumours recurring more often. After adjustment for differences in baseline characteristics, triple negative disease showed worse 10-year OS and triple negative and HER2 positive disease had the lowest 10-year RFS. In the Netherlands, breast cancer subtypes are important predictors for 10-year recurrence rates. Knowledge on recurrence and survival rates according to these different subtypes, in combination with other prognostic factors, can support patient-tailored treatment and individualised follow-up.

Validation of the online prediction model CancerMath in the Dutch breast cancer population.

PURPOSE: CancerMath predicts the expected benefit of adjuvant systemic therapy on overall (OS) and breast cancer-specific survival (BCSS). Here, CancerMath was validated in Dutch breast cancer patients. METHODS: All operated women diagnosed with stage I-III primary invasive breast cancer in 2005 were identified from the Netherlands Cancer Registry. Calibration was assessed by comparing 5- and 10-year predicted and observed OS/BCSS using χ2 tests. A difference > 3% was considered as clinically relevant. Discrimination was assessed by area under the receiver operating characteristic (AUC) curves. RESULTS: Altogether, 8032 women were included. CancerMath underestimated 5- and 10-year OS by 2.2% and 1.9%, respectively. AUCs of 5- and 10-year OS were both 0.77. Divergence between predicted and observed OS was most pronounced in grade II, patients without positive nodes, tumours 1.01-2.00 cm, hormonal receptor positive disease and patients 60-69 years. CancerMath underestimated 5- and 10-year BCSS by 0.5% and 0.6%, respectively. AUCs were 0.78 and 0.73, respectively. No significant difference was found in any subgroup. CONCLUSION: CancerMath predicts OS accurately for most patients with early breast cancer although outcomes should be interpreted with care in some subgroups. BCSS is predicted accurately in all subgroups. Therefore, CancerMath can reliably be used in (Dutch) clinical practice.

Pathologic complete response and overall survival in breast cancer subtypes in stage III inflammatory breast cancer.

PURPOSE: To analyze the influence of hormone receptors (HR) and Human Epidermal growth factor Receptor-2 (HER2)-based molecular subtypes in stage III inflammatory breast cancer (IBC) on tumor characteristics, treatment, pathologic response to neoadjuvant chemotherapy (NACT), and overall survival (OS). METHODS: Patients with stage III IBC, diagnosed in the Netherlands between 2006 and 2015, were classified into four breast cancer subtypes: HR+/HER2- , HR+/HER2+ , HR-/HER2+ , and HR-/HER2- . Patient-, tumor- and treatment-related characteristics were compared. In case of NACT, pathologic complete response (pCR) was compared between subgroups. OS of the subtypes was compared using Kaplan-Meier curves and the log-rank test. RESULTS: 1061 patients with stage III IBC were grouped into subtypes: HR+/HER2- (N = 453, 42.7%), HR-/HER2- (N = 258, 24.3%), HR-/HER2+ (N = 180,17.0%), and HR+/HER2+ (N = 170,16.0%). In total, 679 patients (85.0%) received NACT. In HR-/HER2+ tumors, pCR rate was highest (43%, (p < 0.001). In case of pCR, an improved survival was observed for all subtypes, especially for HR+/HER2+ and HR-/HER2+ tumor subtypes. Trimodality therapy (NACT, surgery, radiotherapy) improved 5-year OS as opposed to patients not receiving this regimen: HR+/HER2- (74.9 vs. 46.1%), HR+/HER2+ (80.4 vs. 52.6%), HR-/HER2+ (76.4 vs. 29.7%), HR-/HER2- (47.6 vs. 27.8%). CONCLUSIONS: In stage III IBC, breast cancer subtypes based on the HR and HER2 receptor are important prognostic factors of response to NACT and OS. Patients with HR-/HER2- IBC were less likely to achieve pCR and had the worst OS, irrespective of receiving most optimal treatment regimen to date (trimodality therapy).

Facilitating validation of prediction models: a comparison of manual and semi-automated validation using registry-based data of breast cancer patients in the Netherlands.

BACKGROUND: Clinical prediction models are not routinely validated. To facilitate validation procedures, the online Evidencio platform ( https://www.evidencio.com ) has developed a tool partly automating this process. This study aims to determine whether semi-automated validation can reliably substitute manual validation. METHODS: Four different models used in breast cancer care were selected: CancerMath, INFLUENCE, Predicted Probability of Axillary Metastasis, and PREDICT v.2.0. Data were obtained from the Netherlands Cancer Registry according to the inclusion criteria of the original development population. Calibration (intercepts and slopes) and discrimination (area under the curve (AUC)) were compared between semi-automated and manual validation. RESULTS: Differences between intercepts and slopes of all models using semi-automated validation ranged from 0 to 0.03 from manual validation, which was not clinically relevant. AUCs were identical for both validation methods. CONCLUSIONS: This easy to use semi-automated validation option is a good substitute for manual validation and might increase the number of validations of prediction models used in clinical practice. In addition, the validation tool was considered to be user-friendly and to save a lot of time compared to manual validation. Semi-automated validation will contribute to more accurate outcome predictions and treatment recommendations in the target population.

Breast conserving therapy and mastectomy revisited: Breast cancer-specific survival and the influence of prognostic factors in 129,692 patients.

This large population-based study compared breast-conserving surgery with radiation therapy (BCT) with mastectomy on (long-term) breast cancer-specific (BCSS) and overall survival (OS), and investigated the influence of several prognostic factors. Patients with primary T1-2N0-2M0 breast cancer, diagnosed between 1999 and 2012, were selected from the Netherlands Cancer Registry. We investigated the 1999-2005 (long-term outcome) and the 2006-2012 cohort (contemporary adjuvant systemic therapy). Cause of death was derived from the Statistics Netherlands (CBS). Multivariable analyses, per time cohort, were performed in T1-2N0-2, and separately in T1-2N0-1 and T1-2N2 stages. The T1-2N0-1 stages were further stratified for age, hormonal receptor and HER2 status, adjuvant systemic therapy and comorbidity. In total, 129,692 patients were included. In the 1999-2005 cohort, better BCSS and OS for BCT than mastectomy was seen in all subgroups, except in patients < 40 years with T1-2N0-1 stage. In the 2006-2012 cohort, superior BCSS and OS were found for T1-2N0-1, but not for T1-2N2. Subgroup analyses for T1-2N0-1 showed superior BCSS and OS for BCT in patients >50 years, not treated with chemotherapy and with comorbidity. Both treatments led to similar BCSS in patients <50 years, without comorbidity and those treated with chemotherapy. Although confounding by severity and residual confounding cannot be excluded, this study showed better long-term BCSS for BCT than mastectomy. Even with more contemporary diagnostics and therapies we identified several subgroups that may benefit from BCT. Our results support the hypothesis that BCT might be preferred in most breast cancer patients when both treatments are suitable.

The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival.

BACKGROUND: The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease-free survival (DFS) in a Dutch population-based cohort. METHODS: All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes. RESULTS: Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38-0.94)) and 42-55 days (HR 0.64 (95% CI: 0.45-0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42-55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days. CONCLUSIONS: Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned.

10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: None.

External validation of 87 clinical prediction models supporting clinical decisions for breast cancer patients.

INTRODUCTION: Numerous prediction models have been developed to support treatment-related decisions for breast cancer patients. External validation, a prerequisite for implementation in clinical practice, has been performed for only a few models. This study aims to externally validate published clinical prediction models using population-based Dutch data. METHODS: Patient-, tumor- and treatment-related data were derived from the Netherlands Cancer Registry (NCR). Model performance was assessed using the area under the receiver operating characteristic curve (AUC), scaled Brier score, and model calibration. Net benefit across applicable risk thresholds was evaluated with decision curve analysis. RESULTS: After assessing 922 models, 87 (9%) were included for validation. Models were excluded due to an incomplete model description (n = 262 (28%)), lack of required data (n = 521 (57%)), previously validated or developed with NCR data (n = 45 (5%)), or the associated NCR sample size was insufficient (n = 7 (1%)). The included models predicted survival (33 (38%) overall, 27 (31%) breast cancer-specific, and 3 (3%) other cause-specific), locoregional recurrence (n = 7 (8%)), disease free survival (n = 7 (8%)), metastases (n = 5 (6%)), lymph node involvement (n = 3 (3%)), pathologic complete response (n = 1 (1%)), and surgical margins (n = 1 (1%)). Seven models (8%) showed poor (AUC<0.6), 39 (45%) moderate (AUC:0.6-0.7), 38 (46%) good (AUC:0.7-0.9), and 3 (3%) excellent (AUC≥0.9) discrimination. Using the scaled Brier score, worse performance than an uninformative model was found in 34 (39%) models. CONCLUSION: Comprehensive registry data supports broad validation of published prediction models. Model performance varies considerably in new patient populations, affirming the importance of external validation studies before applying models in clinical practice. Well performing models could be clinically useful in a Dutch setting after careful impact evaluation.

The majority of 922 prediction models supporting breast cancer decision-making are at high risk of bias.

OBJECTIVES: To systematically review the currently available prediction models that may support treatment decision-making in breast cancer. STUDY DESIGN AND SETTING: Literature was systematically searched to identify studies reporting on development of prediction models aiming to support breast cancer treatment decision-making, published between January 2010 and December 2020. Quality and risk of bias were assessed using the Prediction model Risk Of Bias (ROB) Assessment Tool (PROBAST). RESULTS: After screening 20,460 studies, 534 studies were included, reporting on 922 models. The 922 models predicted: mortality (n = 417 45%), recurrence (n = 217, 24%), lymph node involvement (n = 141, 15%), adverse events (n = 58, 6%), treatment response (n = 56, 6%), or other outcomes (n = 33, 4%). In total, 285 models (31%) lacked a complete description of the final model and could not be applied to new patients. Most models (n = 878, 95%) were considered to contain high ROB. CONCLUSION: A substantial overlap in predictor variables and outcomes between the models was observed. Most models were not reported according to established reporting guidelines or showed methodological flaws during the development and/or validation of the model. Further development of prediction models with thorough quality and validity assessment is an essential first step for future clinical application.

Representativeness of trial participants: linking the EORTC boost-no boost trial to the Netherlands cancer registry.

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.