MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.

Time trends in real-world treatment patterns and survival in patients diagnosed with de novo HER2+ metastatic breast cancer: an analysis of the SONABRE registry.

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.

Trastuzumab Resistance in Patients With HER2-Positive Advanced Breast Cancer: Results From the SONABRE Registry.

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.

The prognostic impact of BMI in patients with HR+/HER2- advanced breast cancer: a study of the SONABRE registry.

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/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), or obese (≥ 30.0 kg/m2). 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.

Tumor-agnostic ctDNA levels by mFAST-SeqS in first-line HR-positive, HER2 negative metastatic breast cancer patients as a biomarker for survival.

This prospective cohort study reports aneuploidy score by mFast-SeqS as a strong prognostic marker in MBC patients. mFAST-SeqS is an affordable and easily implementable method for the assessment of total ctDNA levels and, as such, provides an alternative prognostic tool. One mixed cohort (cohort A, n = 45) starting any type of treatment in any line of therapy and one larger cohort (cohort B, n = 129) consisting of patients starting aromatase inhibitors (AI) as first-line therapy were used. mFAST-SeqS was performed using plasma of blood in which CTCs (CellSearch) were enumerated. The resulting aneuploidy score was correlated with categorized CTC count and associated with outcome. The aneuploidy score was significantly correlated with CTC count, but discordance was observed in 31.6% when applying cut-offs of 5. In both cohorts, aneuploidy score was a significant prognostic marker for both PFS and OS. In the Cox regression models, the HR for aneuploidy score for PFS was 2.52 (95% CI: 1.56-4.07), and the HR for OS was 2.37 (95% CI: 1.36-4.14). Results presented here warrant further investigations into the clinical utility of this marker in MBC patients.

Real-world time trends in overall survival, treatments and patient characteristics in HR+/HER2- metastatic breast cancer: an observational study of the SONABRE Registry.

Background: This study aims to evaluate whether changes in therapeutic strategies have improved survival of patients diagnosed with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC) in real-world. Methods: All 1950 patients systemically treated for HR+/HER2- ABC and diagnosed between 2008 and 2019 in eight hospitals were retrieved from the SONABRE Registry (NCT-03577197). Patients were categorized per three-year cohorts based on year of ABC diagnosis. Tests for trend were used to examine differences in baseline characteristics, Kaplan-Meier methods and Cox proportional hazards for survival analyses, and competing-risk methods for 3-year use of systemic therapy. Findings: Over time, patients were older (≥70 years, 37%, n = 169/456 in 2008-2010, 47%, n = 233/493 in 2017-2019, p = 0.004) and more often had multiple metastatic sites at ABC diagnosis (48%, n = 220/456 in 2008-2010, 56%, n = 275/493 in 2017-2019, p = 0.002). Among patients with metachronous metastases the prior exposure to (neo-) adjuvant therapies increased over time (chemotherapy, 38%, n = 138/362 in 2008-2010, 48%, n = 181/376 in 2017-2019, p = <0.001; endocrine therapy, 64%, n = 231/362 in 2008-2010, 72%, n = 271/376 in 2017-2019, p = <0.001). Overall survival significantly improved from median 31.1 months (95% CI:28.2-34.3) for patients diagnosed in 2008-2010 to 38.4 months (95% CI:34.0-41.1) in 2017-2019 (adjusted hazard ratio = 0.76, 95% CI:0.64-0.90; p = 0.001). Three-year use of CDK4/6 inhibitors increased from 0% for patients diagnosed in 2008-2010 to 54% for diagnosis in 2017-2019. Conversely, three-year use of chemotherapy was 50% versus 36%, respectively. Interpretation: Over time, patients diagnosed with HR+/HER2- ABC presented with less favourable patient characteristics. Nevertheless, we observed that overall survival of ABC increased between 2008 and 2019, with increased use of endocrine/targeted therapies. Funding: The SONABRE Registry is supported by the Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer; and Eli Lilly & Co. Funding sources had no role in the writing of the manuscript.

Outcomes for the first four lines of therapy in patients with HER2-positive advanced breast cancer: results from the SONABRE registry.

PURPOSE: We assessed the systemic treatment choices and outcomes in patients diagnosed with human epidermal growth factor receptor-2-positive (HER2 +) advanced breast cancer (ABC), for the first four lines of systemic therapy and by hormone receptor (HR) status. METHODS: We identified 330 patients diagnosed with HER2 + ABC in 2013-2018 in the Southeast of The Netherlands, of whom 64% with HR + /HER2 + and 36% with HR-/HER2 + disease. Overall survival (OS) from start of therapy was calculated using the Kaplan-Meier method. RESULTS: In real world, 95% of patients with HR + /HER2 + and 74% of patients with HR-/HER2 + disease received systemic therapy. In HR + /HER2 + disease, use of endocrine, chemo- and HER2-targeted therapy was , respectively, 64%, 46% and 60% in first line, and 39%, 64% and 75% in fourth line. In HR-/HER2 + disease, 91-96% of patients received chemotherapy and 77-91% HER2-targeted therapy, irrespective of line of therapy. In patients with HR + /HER2 + disease, median OS was 34.9 months (95%CI:25.8-44.0) for the first line and 12.8 months (95%CI:10.7-14.9) for the fourth line. In HR-/HER2 + disease, median OS was 39.9 months (95%CI:23.9-55.8) for the first line and 15.2 months (95%CI:10.9-19.5) for the fourth line. For patients treated with first-line pertuzumab, trastuzumab plus chemotherapy, median OS was not reached at 56.0 months in HR + /HER2 + disease and 48.4 months (95%CI:32.6-64.3) in HR-/HER2 + disease. CONCLUSION: Survival times for later lines of therapy are surprisingly long and justify the use of multiple lines of systemic therapy in well-selected patients with HER2 + ABC. Our real-world evidence adds valuable observations to the accumulating evidence that within HER2 + ABC, the HR status defines two distinct disease subtypes.

Development of a Clinical Prediction Model for 1-Year Mortality in Patients With Advanced Cancer.

Importance: To optimize palliative care in patients with cancer who are in their last year of life, timely and accurate prognostication is needed. However, available instruments for prognostication, such as the surprise question ("Would I be surprised if this patient died in the next year?") and various prediction models using clinical variables, are not well validated or lack discriminative ability. Objective: To develop and validate a prediction model to calculate the 1-year risk of death among patients with advanced cancer. Design, Setting, and Participants: This multicenter prospective prognostic study was performed in the general oncology inpatient and outpatient clinics of 6 hospitals in the Netherlands. A total of 867 patients were enrolled between June 2 and November 22, 2017, and followed up for 1 year. The primary analyses were performed from October 9 to 25, 2019, with the most recent analyses performed from June 19 to 22, 2022. Cox proportional hazards regression analysis was used to develop a prediction model including 3 categories of candidate predictors: clinician responses to the surprise question, patient clinical characteristics, and patient laboratory values. Data on race and ethnicity were not collected because most patients were expected to be of White race and Dutch ethnicity, and race and ethnicity were not considered as prognostic factors. The models' discriminative ability was assessed using internal-external validation by study hospital and measured using the C statistic. Patients 18 years and older with locally advanced or metastatic cancer were eligible. Patients with hematologic cancer were excluded. Main Outcomes and Measures: The risk of death by 1 year. Results: Among 867 patients, the median age was 66 years (IQR, 56-72 years), and 411 individuals (47.4%) were male. The 1-year mortality rate was 41.6% (361 patients). Three prediction models with increasing complexity were developed: (1) a simple model including the surprise question, (2) a clinical model including the surprise question and clinical characteristics (age, cancer type prognosis, visceral metastases, brain metastases, Eastern Cooperative Oncology Group performance status, weight loss, pain, and dyspnea), and (3) an extended model including the surprise question, clinical characteristics, and laboratory values (hemoglobin, C-reactive protein, and serum albumin). The pooled C statistic was 0.69 (95% CI, 0.67-0.71) for the simple model, 0.76 (95% CI, 0.73-0.78) for the clinical model, and 0.78 (95% CI, 0.76-0.80) for the extended model. A nomogram and web-based calculator were developed to support clinicians in adequately caring for patients with advanced cancer. Conclusions and Relevance: In this study, a prediction model including the surprise question, clinical characteristics, and laboratory values had better discriminative ability in predicting death among patients with advanced cancer than models including the surprise question, clinical characteristics, or laboratory values alone. The nomogram and web-based calculator developed for this study can be used by clinicians to identify patients who may benefit from palliative care and advance care planning. Further exploration of the feasibility and external validity of the model is needed.

The initial hormone receptor/HER2 subtype is the main determinator of subtype discordance in advanced breast cancer: a study of the SONABRE registry.

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.

Quantification of ribociclib in dried blood spots by LC-MS/MS: Method development and clinical validation.

A reliable, specific, selective and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of ribociclib in both dried blood spot (DBS) samples and potassium EDTA plasma. DBS samples were obtained simultaneously with a plasma sample in advanced breast cancer patients treated with ribociclib. A 6 mm disk from the central part of the dried blood spot sample was punched, followed by extraction of ribociclib using liquid-liquid extraction spiked with ribociclib-d6 as internal standard. Concentrations of ribociclib in DBS samples were correlated with corresponding plasma concentrations. From the blood sample also hematocrit was determined. The method was validated for selectivity, sensitivity, precision, lower limit of detection, linearity, stability and accuracy according to the food and drug administration (FDA) guideline. The within- and between-run precisions were ≤10.6 and ≤1.07 %, respectively; while the average accuracy ranged from 100 to 103 %. The influence of hematocrit on validation parameters was tested in the range of 0.20 - 0.40 L/L. No influence of hematocrit on validation parameters was observed. Regression analysis and a Bland-Altman plot indicated correlation between the results obtained from DBS and plasma samples. A strong correlation (R2 >0.97) between DBS samples and plasma concentration from 17 breast cancer patients was found. A number of 12 out of 17 processed DBS samples (71 %) fell inside the acceptable range of 20 % difference of simultaneously obtained plasma samples. The lower limit of quantification in DBS is 10.0 ng/mL and linearity was demonstrated up to 1000 ng/mL. In conclusion, the newly developed assay met the required standard for validation. The methods were used to study ribociclib disposition in patients with advanced breast cancer.

Survival before and after the introduction of pertuzumab and T-DM1 in HER2-positive advanced breast cancer, a study of the SONABRE Registry.

PURPOSE: Immediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to examine whether the real-world overall survival (OS) has improved in patients with human epidermal growth factor receptor 2-positive (HER2 +) advanced breast cancer (ABC) since the market release of pertuzumab and T-DM1. Furthermore, we aimed to assess the implementation and survival rates per hormone receptor (HR) subtype. PATIENTS AND METHODS: We included 493 systemically treated patients consecutively diagnosed with HER2 + ABC in 2008-2017 from the SOutheast Netherlands Advanced BREast cancer (SONABRE) Registry. Median OS was obtained using the Kaplan-Meier method and differences between periods (2008-2012 versus 2013-2017) were tested using multivariable Cox proportional hazards regression modeling. The 3-year implementation rates were estimated for any HER2-targeted therapy, pertuzumab, and T-DM1 by using the competing risk method and calculated from the date of diagnosis of ABC to start of HER2-targeted therapy of interest. RESULTS: The median OS in 2008-2012 versus 2013-2017 was 28.3 versus 39.7 months in all patients (adjusted hazard ratio (adjHR) 0.85, 95%CI 0.66-1.08), 29.9 versus 36.3 months in patients with HR + /HER2 + disease (adjHR 0.97, 95%CI 0.72-1.32), and 22.7 versus 40.9 months in patients with HR-/HER2 + disease (adjHR 0.59, 95%CI 0.38-0.92). Any HER2-targeted therapy was used in 79% of patients in 2008-2012 and in 84% in 2013-2017. The use of pertuzumab and T-DM1 in 2013-2017 was 48% and 29%, respectively. For patients diagnosed with HR + /HER2 + and HR-/HER2 + disease, implementation rates in 2013-2017 were , respectively, 77% and 99% for any HER2-targeted therapy, 38% and 69% for pertuzumab, and 24% and 40% for T-DM1. CONCLUSION: The survival of patients with HER2 + ABC improved since the introduction of pertuzumab and T-DM1. There is room for improvement in implementation of these HER2-targeted therapies, especially in patients with HR + /HER2 + disease.

Disease-free and overall survival after neoadjuvant chemotherapy in breast cancer: breast-conserving surgery compared to mastectomy in a large single-centre cohort study.

PURPOSE: The extended role of breast-conserving surgery (BCS) in the neoadjuvant setting may raise concerns on the oncologic safety of BCS compared to mastectomy. This study compared long-term outcomes after neoadjuvant chemotherapy (NAC) between patients treated with BCS and mastectomy. METHODS: All breast cancer patients treated with NAC from 2008 until 2017 at the Amphia Hospital (the Netherlands) were included. Disease-free and overall survival were compared between BCS and mastectomy with survival functions. Multivariable Cox proportional hazard regression was performed to determine prognostic variables for disease-free survival. RESULTS: 561 of 612 patients treated with NAC were eligible: 362 (64.5%) with BCS and 199 (35.5%) with mastectomy. Median follow-up was 6.8 years (0.9-11.9). Mastectomy patients had larger tumours and more frequently node-positive or lobular cancer. Unadjusted five-year disease-free survival was 90.9% for BCS versus 82.9% for mastectomy (p = .004). Unadjusted five-year overall survival was 95.3% and 85.9% (p < .001), respectively. In multivariable analysis, clinical T4 (cT4) (HR 3.336, 95% CI 1.214-9.165, p = .019) and triple negative disease (HR 5.946, 95% CI 2.703-13.081, p < .001) were negative predictors and pathologic complete response of the breast (HR 0.467, 95% CI 0.238-0.918, p = .027) and axilla (HR 0.332, 95% CI 0.193-0.572, p = .001) were positive predictors for disease-free survival. Mastectomy versus BCS was not a significant predictor for disease-free survival when adjusted for the former variables (unadjusted HR 2.13 (95%CI: 1.4-3.24), adjusted HR 1.31 (95%CI: 0.81-2.13)). In the BCS group, disease-free and overall survival did not differ significantly between cT1, cT2 or cT3 tumours. CONCLUSION: BCS does not impair disease-free and overall survival in patients treated with NAC. Tumour biology and treatment response are significant prognostic indicators.

Quality of life and illness perceptions in patients with breast cancer using a fasting mimicking diet as an adjunct to neoadjuvant chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial.

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.

Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial.

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.

Impact on Quality of Documentation and Workload of the Introduction of a National Information Standard for Tumor Board Reporting.

PURPOSE: Tumor boards, clinical practice guidelines, and cancer registries are intertwined cancer care quality instruments. Standardized structured reporting has been proposed as a solution to improve clinical documentation, while facilitating data reuse for secondary purposes. This study describes the implementation and evaluation of a national standard for tumor board reporting for breast cancer on the basis of the clinical practice guideline and the potential for reusing clinical data for the Netherlands Cancer Registry (NCR). METHODS: Previously, a national information standard for breast cancer was derived from the corresponding Dutch clinical practice guideline. Using data items from the information standard, we developed three different tumor board forms: preoperative, postoperative, and postneoadjuvant-postoperative. The forms were implemented in Amphia Hospital's electronic health record. Quality of clinical documentation and workload before and after implementation were compared. RESULTS: Both draft and final tumor board reports were collected from 27 and 31 patients in baseline and effect measurements, respectively. Completeness of final reports increased from 39.5% to 45.4% (P = .04). The workload for tumor board preparation and discussion did not change significantly. Standardized tumor board reports included 50% (61/122) of the data items carried in the NCR. An automated process was developed to upload information captured in tumor board reports to the NCR database. CONCLUSION: This study shows implementation of a national standard for tumor board reports improves quality of clinical documentation, without increasing clinical workload. Simultaneously, our work enables data reuse for secondary purposes like cancer registration.

Addition of zoledronic acid to neoadjuvant chemotherapy is not beneficial in patients with HER2-negative stage II/III breast cancer: 5-year survival analysis of the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: Adjuvant bisphosphonates are associated with improved breast cancer survival in postmenopausal patients. Addition of zoledronic acid (ZA) to neoadjuvant chemotherapy did not improve pathological complete response in the phase III NEOZOTAC trial. Here we report the results of the secondary endpoints, disease-free survival, (DFS) and overall survival (OS). PATIENTS AND METHODS: Patients with HER2-negative, stage II/III breast cancer were randomized to receive the standard 6 cycles of neoadjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy with or without 4 mg intravenous (IV) ZA administered within 24 h of chemotherapy. This was repeated every 21 days for 6 cycles. Cox regression models were used to evaluate the effect of ZA and covariates on DFS and OS. Regression models were used to examine the association between insulin, glucose, insulin growth factor-1 (IGF-1) levels, and IGF-1 receptor (IGF-1R) expression with survival outcomes. RESULTS: Two hundred forty-six women were eligible for inclusion. After a median follow-up of 6.4 years, OS for all patients was significantly worse for those who received ZA (HR 0.468, 95% CI 0.226-0.967, P = 0.040). DFS was not significantly different between the treatment arms (HR 0.656, 95% CI 0.371-1.160, P = 0.147). In a subgroup analysis of postmenopausal women, no significant difference in DFS or OS was found for those who received ZA compared with the control group (HR 0.464, 95% CI 0.176-1.222, P = 0.120; HR 0.539, 95% CI 0.228-1.273, P = 0.159, respectively). The subgroup analysis of premenopausal patients was not significantly different for DFS and OS ((HR 0.798, 95% CI 0.369-1.725, P = 0.565; HR 0.456, 95% CI 0.156-1.336, P = 0.152, respectively). Baseline IGF-1R expression was not significantly associated with DFS or OS. In a predefined additional study, lower serum levels of insulin were associated with improved DFS (HR 1.025, 95% CI 1.005-1.045, P = 0.014). CONCLUSIONS: Our results suggest that ZA in combination with neoadjuvant chemotherapy was associated with a worse OS in breast cancer (both pre- and postmenopausal patients). However, in a subgroup analysis of postmenopausal patients, ZA treatment was not associated with DFS or OS. Also, DFS was not significantly different between both groups. IGF-1R expression in tumor tissue before and after neoadjuvant treatment did not predict survival. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01099436 , April 2010.

Body composition is associated with risk of toxicity-induced modifications of treatment in women with stage I-IIIB breast cancer receiving chemotherapy.

PURPOSE: Initial dose of chemotherapy is planned based on body surface area, which does not take body composition into account. We studied the association between fat mass (kg and relative to total body weight) as well as lean mass (kg and relative to total body weight) and toxicity-induced modifications of treatment in breast cancer patients receiving chemotherapy. METHODS: In an observational study among 172 breast cancer patients (stage I-IIIB) in the Netherlands, we assessed body composition using dual-energy X-ray scans. Information on toxicity-induced modifications of treatment, defined as dose reductions, cycle delays, regimen switches, or premature termination of chemotherapy, was abstracted from medical records. Adjusted hazard ratios and 95% confidence intervals (95% CI) were calculated to assess associations between body composition and the risk of toxicity-induced modifications of treatment. RESULTS: In total, 95 out of 172 (55%) patients experienced toxicity-induced modifications of treatment. Higher absolute and relative fat mass were associated with higher risk of these modifications (HR 1.14 per 5 kg; 95% CI 1.04-1.25 and HR 1.21 per 5%; 95% CI 1.05-1.38, respectively). A higher relative lean mass was associated with a lower risk of modifications (HR 0.83 per 5%; 95% CI 0.72-0.96). There was no association between absolute lean mass and risk of toxicity-induced modifications of treatment. CONCLUSIONS: A higher absolute and a higher relative fat mass was associated with an increased risk of toxicity-induced modifications of treatment. Absolute lean mass was not associated with risk of these treatment modifications, while higher relative lean mass associated with lower risk of modifications. These data suggest that total fat mass importantly determines the risk of toxicities during chemotherapy in breast cancer patients.

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

A randomized phase 2 study exploring the role of bevacizumab and a chemotherapy-free approach in HER2-positive metastatic breast cancer: The HAT study (BOOG 2008-2003), a Dutch Breast Cancer Research Group trial.

BACKGROUND: To explore the role of bevacizumab and a chemotherapy-free approach, the authors evaluated the combination of bevacizumab, trastuzumab, and paclitaxel (HAT) and the regimen of trastuzumab and bevacizumab (HA) with the addition of paclitaxel after progression (HA-HAT) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. METHODS: In a noncomparative phase 2 trial, patients were randomized between HAT and HA-HAT. The primary endpoint was the progression-free rate at 1 year (1-year PFR). In the HA-HAT group, progression-free survival (PFS) was separately established for HA (PFS1) and HAT (PFS2). RESULTS: Eighty-four patients received HAT (n = 39) or HA-HAT (n = 45). The 1-year PFR was 74.4% (95% confidence interval [CI], 61.8%-89.4%) and 62.2% (95% CI, 49.6%-89.4%) in the HAT and HA-HAT arms, respectively. The median PFS was 19.8 months (95% CI, 14.9-25.6 months) in the HAT arm and 19.6 months (95% CI, 12.0-32.0 months) in the HA-HAT arm. In the HA-HAT arm, the median PFS1 was 10.4 months (95% CI, 6.2-15.0 months), and the median PFS2 was 8.2 months (95% CI, 7.0-12.6 months). The number and severity of adverse events were comparable between the arms. CONCLUSIONS: Both HAT and HA-HAT have promising activity in patients with HER2-positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration. Cancer 2016;122:2961-2970. © 2016 American Cancer Society.

Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 2010.