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Purpose: The aim was to determine whether the real-world first-line progression-free survival (PFS) of patients diagnosed with de novo human epidermal growth factor receptor 2 positive (HER2+) advanced breast cancer (ABC) has improved since the introduction of pertuzumab in 2013. In addition to PFS, we aimed to determine differences in overall survival (OS) and the use of systemic and locoregional therapies., Methods: Included were patients systemically treated for de novo HER2+ ABC in ten hospitals in 2008-2017 from the SONABRE Registry (NCT-03577197). First-line PFS and OS in 2013-2017 versus 2008-2012 was determined using Kaplan-Meier analyses and multivariable Cox proportional hazards modelling. First-given systemic therapy and the use of locoregional therapy within the first year following diagnosis were determined per period of diagnosis., Results: Median and five-year PFS were 26.6 months and 24% in 2013-2017 (n = 85) versus 14.5 months and 10% in 2008-2012 (n = 81) (adjusted HR = 0.65, 95%CI:0.45-0.94). Median and five-year OS were 61.2 months and 51% in 2013-2017 versus 26.1 months and 28% in 2008-2012 (adjusted HR = 0.55, 95%CI:0.37-0.81). Of patients diagnosed in 2013-2017 versus 2008-2012, 84% versus 60% received HER2-targeted therapy and 59% versus 0% pertuzumab-based therapy as first-given therapy. Respectively, 27% and 23% of patients underwent locoregional breast surgery, and 6% and 7% surgery of a metastatic site during the first year following diagnosis., Conclusion: The prognosis of patients with de novo HER2 + ABC has improved considerably. Since 2013 one in four patients were alive and free from progression on first-given therapy for at least five years., (© 2024. The Author(s).)

Background: This study aims to explore whether first-line pertuzumab use modifies the effect of prior use of (neo-) adjuvant trastuzumab on the PFS of first-line HER2-targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC)., Methods: Patients diagnosed with HER2-positive ABC in 2008 to 2018 in 9 Dutch hospitals were derived from the SONABRE Registry (NCT03577197). Patients diagnosed with de novo metastatic breast cancer were excluded. Patients receiving first-line trastuzumab-based therapy for ABC were selected and divided into trastuzumab naïve (n = 113) and trastuzumab pretreated (n = 112). Progression-free survival (PFS) was compared using multivariable Cox proportional hazard models. The interaction effect of first-line pertuzumab was tested using the likelihood-ratio test., Results: The median follow-up time was 47 months (95% confidence interval [CI]: 42-52). When comparing trastuzumab pretreated with trastuzumab naïve patients, the hazard ratio for first-line progression was 2.07 (CI:1.47-2.92). For trastuzumab pretreated patients who received first-line trastuzumab without pertuzumab, the hazard ratio for progression was 2.60 (95% CI:1.72-3.93), whereas for those who received first-line trastuzumab with pertuzumab the hazard ratio was 1.43 (95% CI: 0.81-2.52) (P interaction = .10)., Conclusions: Prior use of trastuzumab as (neo-)adjuvant treatment had a negative impact on PFS of first-line HER2-targeted therapy outcomes. Adding pertuzumab to first-line trastuzumab-based therapy decreased the negative impact of prior (neo-)adjuvant trastuzumab use on first-line PFS. Further studies are needed to assess the effect of prior (neo-)adjuvant pertuzumab use on the outcomes of first-line pertuzumab-based therapy., Competing Interests: Disclosure Khava I.E. Ibragimova: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer; Eli Lilly; Sandra M.E. Geurts: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer; Eli Lilly; AstraZeneca, Gilead, Daiichi-Sankyo; Marissa Meegdes: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer Eli Lilly; AstraZeneca, Gilead; Aude de Fallois: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer Eli Lilly; AstraZeneca, Gilead; Vivianne C.G. Tjan-Heijnen: Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Accord Healthcare; Novartis BV; Roche; Pfizer Eli Lilly; AstraZeneca; Gilead; Daiichi-Sankyo. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study determines the prognostic impact of body mass index (BMI) in patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced (i.e., metastatic) breast cancer (ABC)., Methods: All patients with HR+/HER2- ABC who received endocrine therapy +-a cyclin-dependent kinase 4/6 inhibitor as first-given systemic therapy in 2007-2020 in the Netherlands were identified from the Southeast Netherlands Advanced Breast Cancer (SONABRE) registry (NCT03577197). Patients were categorised as underweight (BMI: < 18.5 kg/m 2 ), normal weight (18.5-24.9 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ), or obese (≥ 30.0 kg/m 2 ). Overall survival (OS) and progression-free survival (PFS) were compared between BMI classes using multivariable Cox regression analyses., Results: This study included 1456 patients, of whom 35 (2%) were underweight, 580 (40%) normal weight, 479 (33%) overweight, and 362 (25%) obese. No differences in OS were observed between normal weight patients and respectively overweight (HR 0.99; 95% CI 0.85-1.16; p = 0.93) and obese patients (HR 1.04; 95% CI 0.88-1.24; p = 0.62). However, the OS of underweight patients (HR 1.45; 95% CI 0.97-2.15; p = 0.07) tended to be worse than the OS of normal weight patients. When compared with normal weight patients, the PFS was similar in underweight (HR 1.05; 95% CI 0.73-1.51; p = 0.81), overweight (HR 0.90; 95% CI 0.79-1.03; p = 0.14), and obese patients (HR 0.88; 95% CI 0.76-1.02; p = 0.10)., Conclusion: In this study among 1456 patients with HR+/HER2- ABC, overweight and obesity were prevalent, whereas underweight was uncommon. When compared with normal weight, overweight and obesity were not associated with either OS or PFS. However, underweight seemed to be an adverse prognostic factor for OS., (© 2023. The Author(s).)

Purpose: The hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the main parameters in guiding systemic treatment choices in breast cancer, but can change during the disease course. This study aims to evaluate the biopsy rate and receptor subtype discordance rate in patients diagnosed with advanced breast cancer (ABC)., Methods: Patients diagnosed with ABC in seven hospitals in 2007-2018 were selected from the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Multivariable logistic regression analyses were performed to identify factors influencing biopsy and discordance rates., Results: Overall, 60% of 2854 patients had a biopsy of a metastatic site at diagnosis. One of the factors associated with a reduced biopsy rate was the HR + /HER2 + primary tumor subtype (versus HR + /HER2- subtype: OR = 0.68; 95% CI: 0.51-0.90). Among the 748 patients with a biopsy of the primary tumor and a metastatic site, the overall receptor discordance rate was 18%. This was the highest for the HR + /HER2 + primary tumor subtype, with 55%. In 624 patients with metachronous metastases, the HR + /HER2 + subtype remained the only predictor significantly related to a higher discordance rate, irrespective of prior (neo-)adjuvant therapies (OR = 7.49; 95% CI: 3.69-15.20)., Conclusion: The HR + /HER2 + subtype has the highest discordance rate, but the lowest biopsy rate of all four receptor subtypes. Prior systemic therapy was not independently related to subtype discordance. This study highlights the importance of obtaining a biopsy of metastatic disease, especially in the HR + /HER2 + subtype to determine the most optimal treatment strategy., (© 2022. The Author(s).)

Importance: Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade., Objective: To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer., Design, Setting, and Participants: A total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis., Interventions: Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2 days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks., Main Outcomes and Measures: Three-year EFS, OS, and safety., Results: A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%]; P = .04). Two patients treated with anthracyclines developed acute leukemia., Conclusions and Relevance: This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms., Trial Registration: ClinicalTrials.gov Identifier: NCT01996267.

Purpose: In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness perceptions regarding the possible side effects of chemotherapy and the FMD were secondary outcomes of the trial., Methods: 131 patients with HER2-negative stage II/III breast cancer were recruited, of whom 129 were randomly assigned (1:1) to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and the day of neoadjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires EORTC-QLQ-C30 and EORTC-QLQ-BR23; the Brief Illness Perception Questionnaire (BIPQ) and the Distress Thermometer were used to assess these outcomes at baseline, halfway chemotherapy, before the last cycle of chemotherapy and 6 months after surgery., Results: Overall QoL and distress scores declined during treatment in both arms and returned to baseline values 6 months after surgery. However, patients' perceptions differed slightly over time. In particular, patients receiving the FMD were less concerned and had better understanding of the possible adverse effects of their treatment in comparison with patients on a regular diet. Per-protocol analyses yielded better emotional, physical, role, cognitive and social functioning scores as well as lower fatigue, nausea and insomnia symptom scores for patients adherent to the FMD in comparison with non-adherent patients and patients on their regular diet., Conclusions: FMD as an adjunct to neoadjuvant chemotherapy appears to improve certain QoL and illness perception domains in patients with HER2-negative breast cancer. Trialregister ClinicalTrials.gov Identifier: NCT02126449.

Purpose: We aimed to evaluate quality of life (QoL) using the European Quality of Life Five-Dimensions questionnaire (EQ-5D-3L) in a real-world cohort of Dutch advanced breast cancer (ABC) patients. Secondary, we reported differences in QoL between subgroups of patients based on age, comorbidity, tumor-, and treatment characteristics, and assessed the association of duration of metastatic disease and time to death with QoL., Methods: ABC patients who attended the outpatient clinic between October 2010 and May 2011 were asked to fill out the EQ-5D-3L questionnaire. Patient-, disease-, and treatment characteristics were obtained from the medical files. Health-utility scores were calculated. Subgroups were described and compared for utility scores by parametric and non-parametric methods., Results: A total of 92 patients were included with a median utility score of 0.691 (Interquartile range [IQR] 0.244). Patients ≥ 65 years had significantly worse median utility scores than younger patients; 0.638 versus 0.743, respectively (p = 0.017). Moreover, scores were significantly worse for patients with versus those without comorbidity (medians 0.620 versus 0.725, p = 0.005). Utility scores did not significantly differ between subgroups of tumor type, type of systemic treatment, number of previous palliative treatment(s), or number or location of metastatic site(s). The remaining survival was correlated with utility scores (correlation coefficient (r) = 0.260, p = 0.0252), especially in the subgroup < 65 years (r = 0.340, p = 0.0169), whereas there was no significant correlation with time since metastatic diagnosis (r = - 0.106, p = 0.3136)., Conclusion: Within this real-world cross-sectional study, QoL was significantly associated with age, comorbidity, and remaining survival duration. The observation of a lower QoL in ABC patients, possibly indicating the last period of life, may assist clinical decision-making on timing of cessation of systemic antitumor therapy.

Background: In 2013, eribulin was reimbursed under a coverage with evidence development (CED) as third or later chemotherapy line for advanced breast cancer (ABC) patients in the Netherlands because of uncertain cost effectiveness. In 2016, the final decision of reimbursing eribulin was taken without considering the evidence collected during CED research. We analysed the cost effectiveness of eribulin versus non-eribulin chemotherapy, using real-world data. Methods: A three health states (progression-free, progressed disease, dead) partitioned survival model was developed. The SOuth East Netherlands Advanced BREast Cancer (SONABRE) registry informed the effectiveness and costs inputs. Health state utility values were obtained from the literature. Incremental cost-effectiveness ratio (ICER) between the eribulin and matched non-eribulin chemotherapy was estimated. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. The financial risk (i.e., the expected value of perfect information (EVPI) plus the expected monetary loss (eML) associated with reimbursing eribulin) and budget impact associated with reimbursing eribulin were calculated. Results: Eribulin led to higher health benefits (0.07 quality-adjusted life year (QALY)) and costs (€15,321) compared with non-eribulin chemotherapy. This resulted in an ICER of €220,608. At a €80,000 per QALY threshold, the risk of reimbursing eribulin was €9,791 per patient (EVPI €13, eML €9,778). Scaled up to the Dutch population, the estimated annual budget impact was €1.9 million and the annual risk of reimbursing eribulin was €2.7 million. Conclusion: From a Dutch societal perspective, eribulin is not cost effective when considering its list price as third and later chemotherapy line for ABC patients.

Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m -2 , to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90-100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449.

Purpose: We assessed the uptake of fertility preservation (FP), recovery of ovarian function (OFR) after chemotherapy, live birth after breast cancer, and breast cancer outcomes in women with early-stage breast cancer., Methods: Women aged below 41 years and referred to our center for FP counseling between 2008 and 2015 were included. Data on patient and tumor characteristics, ovarian function, cryopreservation (embryo/oocyte) and transfer, live birth, and disease-free survival were collected. Kaplan-Meier analyses were performed for time-to-event analyses including competing risk analyses, and patients with versus without FP were compared using the logrank test., Results: Of 118 counseled women with a median age of 31 years (range 19-40), 34 (29%) chose FP. Women who chose FP had less often children, more often a male partner and more often favorable tumor characteristics. The 5-year OFR rate was 92% for the total group of counseled patients. In total, 26 women gave birth. The 5-year live birth rate was 27% for the total group of counseled patients. Only three women applied for transfer of their cryopreserved embryo(s), in two combined with preimplantation genetic diagnosis (PGD) because of BRCA1-mutation carrier ship. The 5-year disease-free survival rate was 91% versus 88%, for patients with versus without FP (P = 0.42)., Conclusions: Remarkably, most women achieved OFR, probably related to the young age at diagnosis. Most pregnancies occurred spontaneously, two of three women applied for embryo transfer because of the opportunity to apply for PGD.

Objective: In breast cancer patients, treatment at the end of life accounts for a major share of medical spending. However, little is known about the variability of cost trajectories between patients. This study aims to identify underlying latent groups of advanced breast cancer patients with similar cost trajectories over the last year before death., Methods: Data from deceased advanced breast cancer patients, diagnosed between 2010 and 2017, were retrieved from the Southeast Netherlands Advanced Breast Cancer (SONABRE) Registry. Costs of hospital care over the last twelve months before death were analyzed, and the variability of longitudinal patterns between patients were explored using group-based trajectory modeling. Descriptive statistics and multinomial logistic regression were applied to investigate differences between the identified latent groups., Results: We included 558 patients. Over the last twelve months before death, mean hospital costs were €2,255 (SD = €492) per month. Costs increased over the last five months and reached a maximum of €3,614 in the last month of life, driven by hospital admissions, while spending for medication declined over the last three months of life. Based on patients' individual cost trajectories, we identified six latent groups with distinct longitudinal patterns, of which only two showed a marked increase in costs over the last twelve months before death. Latent groups were constituted of heterogeneous patients, and clinical characteristics explained membership only to a limited extent., Conclusions: The average costs of advanced breast cancer patients increased towards the end of life. However, we uncovered several latent groups of patients with divergent cost trajectories, which did not reflect the overall increasing trend. The mechanisms underlying the variability in cost trajectories warrants further research., Competing Interests: The data collection of the Southeast Netherlands Advanced Breast Cancer Registry was funded by the Netherlands Organization for Health Research and Development (ZonMw), Novartis, Pfizer, Roche Nederland B.V., Eisai B.V., and Eli Lilly NL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and this does also not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Eribulin provided significant overall survival (OS) benefit in heavily pretreated advanced breast cancer patients in the EMBRACE trial. We investigated the use of eribulin in daily clinical practice, the relative effectiveness of eribulin versus non-eribulin chemotherapy, and the safety of eribulin in real-world patients included in the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Material and methods: Patients treated with eribulin and eligible patients for eribulin who received a different chemotherapy (i.e., non-eribulin group) in ten hospitals in 2013-2017 were included. A multivariate matching algorithm was applied to correct for differences in baseline characteristics between the groups, including the number of previous treatment lines. Progression-free survival (PFS) and OS of eribulin were compared with the matched non-eribulin group through Kaplan-Meier curves and multivariate Cox proportional hazard models. The occurrence of dose delay and reduction was described. Results: Forty-five patients received eribulin according to its registration criteria and 74 patients were eligible for eribulin but received non-eribulin chemotherapy. Matching increased the similarity in baseline characteristics between the eribulin and non-eribulin groups. Median PFS was 3.5 months (95% confidence interval (CI): 2.7-5.5) in the eribulin group and 3.2 months (95% CI: 2.0-4.8) in the matched non-eribulin group (adjusted hazard ratio (HR): 0.83, 95% CI: 0.49-1.38). Median OS was 5.9 months (95% CI: 4.6-11.0) and 5.2 months (95% CI: 4.6-9.5) in the eribulin and non-eribulin groups, respectively (adjusted HR: 0.66, 95% CI: 0.38-1.13). Dose delay or reduction occurred in 14 patients (31%) receiving eribulin. Conclusions: No difference in PFS and OS was observed between eribulin and non-eribulin treated patients. Eribulin had a manageable toxicity profile.

Purpose: We aimed to assess the implementation and effectiveness of exemestane plus everolimus treatment per hospital type in real-life, shortly after approval of everolimus., Methods: Advanced breast cancer patients treated with exemestane plus everolimus in 2012-2014 were included from the SONABRE registry. Progression-free survival (PFS) and a 12-week conditional PFS (post-hoc) were estimated by Kaplan-Meier method. The multivariable Cox proportional hazards model was performed by type of hospital and adjusted for patient, tumour and treatment characteristics., Results: We included 122 patients, comprising 48 patients treated in academic (N = 1), 56 in teaching (N = 4), and 18 in non-teaching (N = 2) hospitals. The median PFS was 6.3 months (95% Confidence Interval (CI) 4.0-8.6) overall, and 8.5 months (95% CI 7.7-9.3), 4.2 months (95% CI 2.0-6.3), and 5.5 months (95% CI 4.2-6.7) for the patients treated in academic, teaching and non-teaching hospitals, respectively. The adjusted Hazard Ratio (HR) for PFS-events was 1.5 (95% CI 1.0-2.2) and 1.0 (95% CI 0.5-1.9) respectively for patients treated at teaching and non-teaching hospitals versus the academic hospital. The adjusted HR for 12-week conditional PFS-events was not different between hospital types. In the first 12-week treatment period, treatment was discontinued due to early progression in one out of 48 patients in the academic versus nine out of 74 patients in the non-academic hospitals, confirmed by imaging in one and two patients, respectively., Conclusions: In our study, the median PFS was borderline significantly different between hospital types, possibly the result of a different assessment approach in the first 12-week treatment period., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab., Methods: The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m 2 ), epirubicin (90 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) every 3 weeks for three cycles followed by paclitaxel (80 mg/m 2 on days 1 and 8) and carboplatin (area under the concentration-time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing., Findings: Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related., Interpretation: In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results., Funding: Roche Netherlands., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial., Methods: A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted., Results: In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained., Conclusion: According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts., Methods: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only., Results: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle., Conclusion: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles., (The Author(s). Published by S. Karger AG, Basel.)

Communication about palliative treatment options requires a balance between providing patients with sufficient information and not providing unwanted information. Surveys have indicated that many patients with advanced cancer express a wish to receive detailed information. In this prospective multicenter study, the information desire of patients with advanced breast or colorectal cancer was further investigated by offering treatment-related information to patients using a decision aid (DA). In addition, this study explored oncologists' awareness of their patients' information desire. Seventy-seven patients with advanced breast or colorectal cancer facing the decision whether to start second-line palliative chemotherapy were offered a DA by a nurse. This DA contained information on adverse events, tumor response, and survival. The nurse asked the patient whether each information item was desired. Ninety-five percent of patients chose to receive information on adverse events, 91 % chose to receive information on tumor response, and 74 % chose to receive information on survival. Oncologists' judgment of patients' information desire was 100, 97, and 81 %, respectively. For all three information items together, oncologists correctly judged the information desire of 62 % of patients. This study confirms that many patients with advanced cancer wish to receive detailed information on the benefits and risks of palliative treatment options when the information is actually available. Oncologists were adequately aware of this high information desire, but had some difficulty judging the information desire of individual patients. A stepped approach to giving information ("preview, ask, tell, ask") may help to better meet patients' information needs.

Introduction: We assessed the incidence and timing of first cardiac events, impact on trastuzumab prescription, and role of left ventricular ejection fraction (LVEF) monitoring in daily practice of trastuzumab-treated patients with human epidermal growth receptor 2 (HER2)-positive early breast cancer., Methods: We included all patients with stage I-III breast cancer diagnosed in the early years (2005-2007) after the introduction of adjuvant trastuzumab in five hospitals in Southeast Netherlands. We studied the incidence and timing of cardiotoxicity in patients treated with adjuvant trastuzumab, using similar cardiac endpoints as in the Herceptin Adjuvant (HERA) trial., Results: Of 2,684 included patients, 476 (17.7%) had a HER2-positive tumor. Of these, 269 (56.9%) were treated with adjuvant chemotherapy, and of these, 230 (85.5%) also received trastuzumab. Cardiotoxicity was observed in 29 of 230 patients (12.6%). Twenty of the 230 patients (8.7%) had symptomatic cardiotoxicity, defined as a drop in LVEF of at least 10 percentage points and to below 50%, accompanied by symptoms of congestive heart failure. Trastuzumab was definitely discontinued because of supposed cardiotoxicity in 36 patients (15.6%), of whom only 15 (6.5%) had a significant LVEF drop. Of the 36 patients who prematurely discontinued trastuzumab (including the 29 in whom cardiotoxicity was observed), 84.8% stopped in the first 6 months. No cardiac deaths were seen., Conclusion: In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from LVEF outcome. We suggest that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. Nonetheless, further research is needed., Implications for Practice: Knowledge of when cardiotoxicity occurs in daily practice will help shape the best follow-up method for cardiac monitoring in trastuzumab-treated patients with human epidermal growth receptor 2-positive early breast cancer. In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from left ventricular ejection fraction (LVEF) outcome. When cardiotoxicity was found in daily practice, it occurred mainly in the first 6 months after start of trastuzumab. This study suggests that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. This insight stresses the relevance of performing real-world analyses., (©AlphaMed Press.)

Background: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer., Patients and Methods: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test., Results: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors., Conclusions: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: According to surveys, many patients with advanced cancer wish to receive survival information., Objective: This study investigated information preferences by offering patients a decision aid (DA) with information on expected survival for two treatment options: supportive care with or without second-line palliative chemotherapy. Predictors of accepting survival information were explored., Design: Eligible patients in this multicentre prospective study were offered second-line chemotherapy for advanced breast or colorectal cancer. A nurse presented a DA on second-line treatment and asked patients whether they desired information on (i) adverse events, (ii) tumour response and (iii) survival. Data on 50 clinical and psychosocial patient characteristics were collected from inclusion forms and patient questionnaires., Results: Seventy-seven patients received a DA; median age 62 years (range 32-80), 61% female, 77% colorectal cancer. Fifty-seven patients (74%; 95% CI 64-84) desired survival information. Four psychosocial characteristics (e.g. deliberative decision style) independently predicted information desire. However, the use of these characteristics to predict information desire hardly outperformed a simple prediction rule., Conclusions: Many patients desired information on expected survival when deciding about second-line treatment. However, our exploratory analysis indicated that patients desiring this information could not be identified based on their clinical or psychosocial characteristics. These findings can help encourage candid discussions about expected survival. Health professionals should be careful not to make implicit assumptions of information desire based on patient characteristics, but to explicitly ask patients if survival information is desired, and act accordingly., (© 2014 John Wiley & Sons Ltd.)

Background: The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials., Methods: We included all patients with stage I-III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005-2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice., Results: Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37-1.06) for trastuzumab when adjusting for potential confounders., Conclusion: This study shows that in real life, patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment., (©AlphaMed Press.)

Background: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients., Methods: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy., Results: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy., Conclusion: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.

Introduction: Although the effect of hormonal therapy (HT) on fracture risk during treatment of breast cancer is established, information about fracture incidence after completion of HT is scarce. In this hospital based observational study we evaluated fracture rates after completion of HT in pre- and postmenopausal women with breast cancer., Methods: All women diagnosed with breast cancer in the VieCuri Medical Center between 1998 and 2005 who started adjuvant HT with aromatase inhibitors or tamoxifen were included (n = 289). Data on fracture rate, fracture type and risk factors for fracture after completion of HT were collected., Results: The overall fracture rate was 12% in pre- and 15% in postmenopausal women respectively during an average follow-up of 3.1 ± 2.9 years. The number of patients with at least one fracture was 41 (14%). There was no difference in fracture rates between different types of HT (P = 0.15). The most common types of fractures were toe/finger fractures in premenopausal- and hip and major fractures in postmenopausal women. Median time to first fracture was shorter in premenopausal women (1.4 years, IQR 0.2-3.5) than in postmenopausal women (2.4 years, IQR 0.7-5.1, P = 0.01). A history of previous fracture was a significant risk factor for fracture in postmenopausal women (HR 3.9, 95% CI 1.3-11.7)., Conclusion: Fracture rates in the first years after cessation of HT for breast cancer were 12% and 15% for pre- and postmenopausal women respectively. The most common fractures in postmenopausal women were hip and major fractures., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis., Methods: Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented., Results: The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from € 20,658 (95% CI, € 20,049 to € 21,247) to € 17,168 (95% CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G-CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was € 13,112 per patient with episodes of FN prevented., Conclusion: We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented.

Purpose: Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy., Patients and Methods: In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm., Results: After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis)., Conclusion: In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.

Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (-), HR+/HER2+, HR-/HER2+ and triple negative (TN). Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66 % of patients had the HR+/HER2- subtype, 8 % the HR-/HER2+ subtype, 15 % the TN subtype and 11 % the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4 months), compared to 24.8 months for the HR+/HER2- subtype, 19.8 months for the HR-/HER2+ subtype and 8.8 months for the TN subtype (P < 0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.