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.

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.

Real-world palbociclib effectiveness in patients with metastatic breast cancer: Focus on neutropenia-related treatment modification strategies and clinical outcomes.

INTRODUCTION: In addition to clinical trials, real-world data is needed to verify the effectiveness of the CDK 4/6 inhibitor palbociclib. The primary aim was to examine real-world variation in treatment modification strategies for neutropenia and its relation to progression-free survival (PFS). The secondary aim was to assess if there is a gap between real-world and clinical trial outcomes. MATERIALS AND METHODS: In this multicenter, retrospective observational cohort study 229 patients were analyzed who started palbociclib and fulvestrant as second- or later-line therapy for HR-positive, HER2-negative metastatic breast cancer in the Santeon hospital group in the Netherlands between September 2016 and December 2019. Data were manually retrieved from patients' electronic medical records. PFS was examined using the Kaplan-Meier method to compare neutropenia-related treatment modification strategies within the first three months after neutropenia grade 3 - 4 occurred, as well as patients' eligibility to have participated in the PALOMA-3 clinical trial or not. RESULTS: Even though treatment modification strategies differed from those in PALOMA-3 (dose interruptions: 26 vs 54%, cycle delays: 54 vs 36%, and dose reductions: 39 vs 34%), these did not influence PFS. Patients who were PALOMA-3 ineligible experienced a shorter median PFS than those who were eligible (10.2 vs. 14.1 months; HR 1.52; 95% CI 1.12 - 2.07). An overall longer median PFS was found compared to PALOMA-3 (11.6 vs. 9.5 months; HR 0.70; 95% CI 0.54 - 0.90). CONCLUSION: This study suggests no impact of neutropenia-related treatment modifications on PFS and confirms inferior outcomes outside clinical trial eligibility.

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.

Changes in intestinal microbiota in postmenopausal oestrogen receptor-positive breast cancer patients treated with (neo)adjuvant chemotherapy.

This clinical study explored the associations between the intestinal microbiota, chemotherapy toxicity, and treatment response in postmenopausal oestrogen receptor positive breast cancer patients.Oestrogen receptor positive postmenopausal breast cancer patients were prospectively enroled in a multicentre cohort study and treated with 4 cycles of (neo)adjuvant adriamycin, cyclophosphamide (AC) followed by 4 cycles of docetaxel (D). Patients collected a faecal sample and completed a questionnaire before treatment, during AC, during D, and after completing AC-D. Chemotherapy toxicity and tumour response were determined. Intestinal microbiota was analysed by amplicon sequencing of the 16 S rRNA V4 gene-region. In total, 44 patients, including 18 neoadjuvant patients, were included, and 153 faecal samples were collected before AC-D (n = 44), during AC (n = 43), during D (n = 29), and after AC-D treatment (n = 37), 28 participants provided all four samples. In the whole group, observed species richness reduced during treatment (p = 0.042). The abundance of Proteobacteria, unclassified Enterobacterales, Lactobacillus, Ruminococcaceae NK4A214 group, Marvinbryantia, Christensenellaceae R7 group, and Ruminococcaceae UCG-005 changed significantly over time. Patients with any grade diarrhoea during docetaxel treatment had a significantly lower observed species richness compared to patients without diarrhoea. In the small group neoadjuvant treated patients, pathologic response was unrelated to baseline intestinal microbiota richness, diversity and composition. While the baseline microbiota was not predictive for pathologic response in a rather small group of neoadjuvant treated patients in our study, subsequent shifts in microbial richness, as well as the abundance of specific bacterial taxa, were observed during AC-D treatment in the whole group and the neoadjuvant group.

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.

The implementation of CDK 4/6 inhibitors and its impact on treatment choices in HR+/HER2- advanced breast cancer patients: A study of the Dutch SONABRE Registry.

In August 2017, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have been reimbursed in the Netherlands for patients with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC). This study evaluates the implementation of CDK4/6 inhibitors and changes in treatment choices in the Netherlands. All patients diagnosed with HR+/HER2- ABC in 2009 to 2018 in seven hospitals were selected from the Southeast Netherlands Advanced Breast cancer (SONABRE) registry. The 2-year cumulative use of CDK4/6 inhibitors since reimbursement date (August 2017) was assessed using competing-risk methodology in two cohorts. The first cohort included patients with ABC diagnosis between August 2017 and December 2018. The second cohort included patients with ABC diagnosis between 2009 and August 2017, and still alive on August 1, 2017. In addition, treatment choices in the first three lines of therapy in calendar years 2009 to 2018 were evaluated for the total study population. Among patients diagnosed since August 2017 (n = 214), 50% (95% confidence interval [CI] = 43-57) received CDK4/6 inhibitors within 2 years beyond diagnosis. Of eligible patients diagnosed before August 2017 (n = 417), 31% (95% CI = 27-36) received CDK4/6 inhibitors within 2 years following reimbursement. Another 20% of both cohorts are still CDK4/6 inhibitor naïve and on first-line therapy. The use of chemotherapy decreased in first two lines of therapy between 2009 and 2018 (first-line: 29%-13%; second-line: 26%-19%). The implementation rate of CDK4/6 inhibitors since reimbursement is currently 50% within 2 years beyond diagnosis and is expected to increase further. The implementation of targeted therapy decreased the use of chemotherapy as first-line therapy.

Intestinal Microbiota in Postmenopausal Breast Cancer Patients and Controls.

BACKGROUND: Previous preclinical and clinical research has investigated the role of intestinal microbiota in carcinogenesis. Growing evidence exists that intestinal microbiota can influence breast cancer carcinogenesis. However, the role of intestinal microbiota in breast cancer needs to be further investigated. This study aimed to identify the microbiota differences between postmenopausal breast cancer patients and controls. PATIENTS AND METHODS: This prospective cohort study compared the intestinal microbiota richness, diversity, and composition in postmenopausal histologically proven ER+/HER2- breast cancer patients and postmenopausal controls. Patients scheduled for (neo)adjuvant adriamycin, cyclophosphamide (AC), and docetaxel (D), or endocrine therapy (tamoxifen) were prospectively enrolled in a multicentre cohort study in the Netherlands. Patients collected a faecal sample and completed a questionnaire before starting systemic cancer treatment. Controls, enrolled from the National Dutch Breast Cancer Screening Programme, also collected a faecal sample and completed a questionnaire. Intestinal microbiota was analysed by amplicon sequencing of the 16S rRNA V4 gene region. RESULTS: In total, 81 postmenopausal ER+/HER2- breast cancer patients and 67 postmenopausal controls were included, resulting in 148 faecal samples. Observed species richness, Shannon index, and overall microbial community structure were not significantly different between breast cancer patients and controls. There was a significant difference in overall microbial community structure between breast cancer patients scheduled for adjuvant treatment, neoadjuvant treatment, and controls at the phylum (p = 0.042) and genus levels (p = 0.015). Dialister (p = 0.001) and its corresponding family Veillonellaceae (p = 0.001) were higher in patients scheduled for adjuvant treatment, compared to patients scheduled for neoadjuvant treatment. Additional sensitivity analysis to correct for the potential confounding effect of prophylactic antibiotic use, indicated no differences in microbial community structure between patients scheduled for neoadjuvant systemic treatment, adjuvant systemic treatment, and controls at the phylum (p = 0.471) and genus levels (p = 0.124). CONCLUSIONS: Intestinal microbiota richness, diversity, and composition are not different between postmenopausal breast cancer patients and controls. The increased relative abundance of Dialister and Veillonellaceae was observed in breast cancer patients scheduled for adjuvant treatment, which might be caused by a relative decrease in other bacteria due to prophylactic antibiotic administration rather than an absolute increase.

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.

An economic evaluation of eribulin for advanced breast cancer treatment based on the Southeast Netherlands advanced breast cancer registry.

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.

Variability of cost trajectories over the last year of life in patients with advanced breast cancer in the Netherlands.

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.

Preserving fertility in young women undergoing chemotherapy for early breast cancer; the Maastricht experience.

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.

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.

The administration of adjuvant chemo(-immuno) therapy in the post ACOSOG-Z0011 era; a population based study.

PURPOSE: The ACOSOG-Z0011-study has resulted in a trend to a more conservative treatment of the axilla for selected sentinel-node-positive patients. However, axillary nodal involvement has always been an important factor for tumor staging and tailoring adjuvant chemotherapy plans. This study evaluates the impact of omitting completion axillary lymph node dissection (cALND) on the administration of adjuvant chemo (-immuno)therapy in Dutch clinical T1-2N0M0 (cT1-2N0M0) sentinel-node-positive breast cancer patients. METHODS: Data were obtained from the nationwide NABON breast cancer audit. Descriptive analyses were used to demonstrate trends in axillary surgery and adjuvant chemo (-immuno)therapy. Multivariable logistic regression analyses were used to identify factors associated with the prescription of chemo (-immuno)therapy. RESULTS: In this cohort of 4331 patients, the omission of a cALND increased from 34% to 92%, and the administration of chemo (-immuno)therapy decreased from 68% to 55%, between 2011 and 2015 (P < 0.001). Patients treated with cALND had an OR of 2.2 for receiving adjuvant chemo (-immuno)therapy compared with SLNB only patients. Lower age, a hormone receptor (HR) status other than HR-positive, HER2-negative, increasing tumor grade and stage, and a lymph node status ≥ pN2 were independently associated with a higher probability of chemo (-immuno)therapy (P < 0.05). CONCLUSIONS: This study showed that Dutch cT1-2N0M0 sentinel node-positive breast cancer patients treated with cALND had a higher independent probability for receiving adjuvant chemo (-immuno)therapy compared with SLNB only patients, even when corrected for lymph node status and HR-status. Probably, the decisions to administer adjuvant chemo (-immuno)therapy were not only based on guidelines and tumor characteristics, but also on the preferences from physicians and patients.

Axillary staging in breast cancer patients treated with neoadjuvant chemotherapy in two Dutch phase III studies.

BACKGROUND: Primary aim of our study was to assess the impact of timing of sentinel node procedure, pre- versus post-neoadjuvant chemotherapy, on final pathologic node-negative rate (pN0) in patients with clinically node-negative (cN0) breast cancer. Secondary endpoint was the usability of the sentinel node procedure in patients with clinically node-positive disease that converted to cN0 after neoadjuvant chemotherapy. PATIENTS AND METHODS: Patients were enrolled in two sequentially conducted Dutch phase III trials, studying the impact of two neoadjuvant chemotherapy schedules and use of zoledronic acid on complete pathologic response rate. For the present analyses, patients were excluded if they had not undergone surgical axillary staging. RESULTS: In total 439 patients were included, of whom 230 (52%) had pre-treatment cN0. In this group, pN0 status was seen in 58% (N = 23) of patients with a sentinel node biopsy post-neoadjuvant chemotherapy compared to 51% (N = 83) pre-neoadjuvant chemotherapy, including the axillary lymph node dissection whenever performed. In multivariable analysis, timing of sentinel node procedure (pre- versus post- neoadjuvant chemotherapy) was, however, not significantly associated with final pN0/pN0(i+) status, with an odds ratio of 1.18 (95% CI 0.64 - 2.18) after correction for age, clinical tumor status, histology, grade, hormone- and HER2 receptor. Of patients with clinically node-positive disease only 15% had a final pN0 status, with a false-negative rate of the sentinel node of 30%. CONCLUSION: In breast cancer patients with cN0 disease, sentinel node procedure performed post-neoadjuvant chemotherapy led to nodal down staging, although not statistically significant after multivariate correction for patient and tumor characteristics.

Ultrasound is at least as good as magnetic resonance imaging in predicting tumour size post-neoadjuvant chemotherapy in breast cancer.

BACKGROUND: The aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported. METHODS: Patients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n=155), US (n=123), and histopathological tumour size. RESULTS: MRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P25=26, P75=100) and 49% (P25=22, P75=100) for MRI and US, respectively (P=0.06). CONCLUSIONS: In this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977).

If there is no overall survival benefit in metastatic breast cancer: does it imply lack of efficacy? Taxanes as an example.

In recent years, new drugs have shown activity in metastatic breast cancer, but not always resulting in an overall survival benefit. This has led to discussions if such drugs, mainly expensive drugs, should be reimbursed especially when also not leading to improvement in quality of life. For that reason, we decided to systematically review taxane-based chemotherapy studies in early and metastatic breast cancer, to assess which factors may have caused the differential outcome. Taxanes did not improve survival in metastatic breast cancer trials, whereas they did so in early breast cancer trials. We questioned if the differential outcome of taxanes in metastatic breast cancer might be caused by the chosen comparator and study design. We noticed that in the majority of metastatic breast cancer studies taxanes were used as a substitute for other active cytotoxic drugs, mainly cyclophosphamide, whereas in early breast cancer studies taxanes were generally delivered in addition to a standard regimen. We conclude from our analyses that use of taxanes instead of other active drugs explains the lack of overall survival benefit in metastatic breast cancer trials. Further, our results suggest that cyclophosphamide is an important drug in the treatment of breast cancer, being as effective as optimally dosed taxanes and anthracyclines. By studying the different study designs and comparators in both settings, we were able to demonstrate their impact on efficacy endpoints. We conclude, therefore, that re-assessment of studies of drugs both assessed in metastatic and early breast cancer provides a new tool for improved understanding.

Taxane resistance in breast cancer: a closed HER2 circuit?

Microtubule inhibitors, such as the taxanes docetaxel and paclitaxel, are commonly used drugs for the treatment of breast cancer. Although highly active in a large fraction of individuals a considerable number of patients show poor response due to either intrinsic or acquired drug resistance. Extensive research in the past identified several taxane resistance-related mechanisms being activated by pathologically altered single gene function. To date, however, a clinically relevant predictive biomarker for taxanes has not been derived yet from this knowledge, most likely due to the manifold of resistance mechanisms that may combine in one tumor, thereby fostering escape from taxane cytotoxicity. Here, we aimed to comprehensively review the current literature on taxane resistance mechanisms in breast cancer. Interestingly, besides altered microtubule physiology we identified the HER2 signaling cascade as a major dominator influencing several routes of cytotoxicity escape, such as cell survival, apoptosis, drug efflux, and drug metabolism. Furthermore, the transcription factor YBX-1, activated by HER2, facilitates a sustaining HER2 signaling feedback loop contributing to the establishment of cellular survival detours. In conclusion, taxane resistance in breast cancer follows a multiplex establishment of drug cytotoxicity escape routes, which may be most efficiently therapeutically targeted by interference with their mutually governing signaling nodes.