http://repub.eur.nl/res/aut/25176/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37206/ 2012-01-01T00:00:00Z OBJECTIVE: The impact of axillary treatment in daily practice on 5-year regional recurrence rate in breast cancer patients with isolated tumor cells or micrometastases in the sentinel node (SLN). BACKGROUND: Axillary dissection is recommended in patients with tumor-positive SLNs. But, in recent studies, regional recurrence rates seemed low if dissection was omitted. METHODS: We identified all patients in The Netherlands with invasive breast cancer who had an SLN biopsy before 2006, favorable primary tumor characteristics, and node-negative disease, isolated tumor cells or micrometastases as final nodal status. The primary endpoint was regional recurrence rate. To investigate differences in recurrence rates between patients with and without axillary treatment, a proportional hazard regression was carried out correcting for potential confounders. RESULTS: In total, 857 patients with node-negative disease, 795 patients with isolated tumor cells, and 1028 patients with micrometastases in the SLN were included. Without axillary treatment, the 5-year regional recurrence rates were 2.3%, 2.0%, and 5.6%, respectively. Compared with patients who underwent axillary treatment, the adjusted hazard ratio for regional recurrence in patients who underwent an SLN procedure only was 1.08 (95% CI, 0.23-4.98) for node-negative disease, 2.39 (95% CI, 0.67-8.48) for isolated tumor cells, and 4.39 (95% CI, 1.46-13.24) for micrometastases. Doubling of tumor size, grade 3 and negative hormone receptor status were also significantly associated with recurrence. CONCLUSIONS: Not performing axillary treatment in patients with SLN micrometastases is associated with an increased 5-year regional recurrence rate. Axillary treatment is recommended in patients with SLN micrometastases and unfavorable tumor characteristics. Copyright http://repub.eur.nl/res/pub/33584/ 2011-12-01T00:00:00Z Purpose: Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective longitudinal study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence-free survival. Methods: Sera of 82 breast cancer patients obtained after surgery, but prior to the administration of adjuvant therapy, were fractionated using anion-exchange chromatography, to facilitate the detection of the low-abundant serum peptides. Selected fractions were subsequently analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS), and the resulting protein profiles were searched for prognostic markers by appropriate bioinformatics tools. Results: Four peak clusters (i.e. m/z 3073, m/z 3274, m/z 4405 and m/z 7973) were found to bear significant prognostic value (P ≤ 0.01). The m/z 3274 candidate marker was structurally identified as inter-alpha-trypsin inhibitor heavy chain 4 fragment658-688in serum. Except for the m/z 7973 peak cluster, these peaks remained independently associated with recurrence-free survival upon multivariate Cox regression analysis, including clinical parameters of known prognostic value in this study population. Conclusion: Investigation of the postoperative serum proteome by, e.g., anion-exchange fractionation followed by SELDI-TOF MS analysis is promising for the detection of novel prognostic factors. However, regarding the rather limited study population, validation of these results by analysis of independent study populations is warranted to assess the true clinical applicability of discovered prognostic markers. In addition, structural identification of the other markers will aid in elucidation of their role in breast cancer prognosis, as well as enable development of absolute quantitative assays. http://repub.eur.nl/res/pub/20912/ 2010-09-01T00:00:00Z Background: To describe variation in staging and primary treatment by hospital characteristics including type and volume and region in patients with early breast cancer (BC) in the Netherlands, 2003-2006 after completion of national guidelines in 2002. Methods: All patients newly diagnosed with invasive BC in 2003-2006 and recorded in the Netherlands Cancer Registry were included (n = 51 354). Multivariable logistic regression analyses examined the influence of patient and hospital characteristics, also by region, on type of breast surgery, axillary lymph node dissection (ALND), sentinel node procedure (SNP), and adjuvant irradiation and/or systemic treatment. Results: Patients <40 years more often underwent breast conserving surgery (BCS) in general hospitals (OR 1.4 (95%CI 1.1-1.5)) than in teaching and academic hospitals, whereas patients of 40-69 years less often received BCS in an academic hospital (OR 0.9 (95%CI 0.8-1.0)) than in teaching hospitals. Patients with pT1-2N0 cancer more often underwent primary ALND in a general hospital than in a larger teaching or academic hospital. Type of hospital did not seem to affect utilization of adjuvant systemic therapy, but patient age and tumour size and grade did. Over time, patients more often received SNP, BCS, and adjuvant systemic therapy, primary ALND being on the decline, but with substantial regional variation between geographic regions. Conclusion: With detailed evidence-based national guidelines since 2002 the considerable regional and hospital variation in staging procedures and primary treatment among newly diagnosed patients with early breast cancer in the Netherlands decreased markedly, suggesting the presence of late adaptors rather than specific hospital characteristics. http://repub.eur.nl/res/pub/20729/ 2010-06-01T00:00:00Z Introduction: Geographic transferability of model-based cost-effectiveness results may facilitate and shorten the reimbursement process of new pharmaceuticals. This study provides a real world example of transferring a cost-effectiveness study of trastuzumab for the adjuvant treatment of HER2-positive early breast cancer from the United Kingdom to The Netherlands. Methods: Three successive steps were taken. Step 1: Collect available information with regard to the original model, and assess transferability using existing checklists. Step 2: Adapt transferability-limiting factors. Step 3: Obtain a country-specific estimate of cost-effectiveness. Results: The structure of the UK model was transferable, although some of the model inputs needed adaptation. From a health-care perspective, the Dutch estimate amounted to €5828/quality-adjusted life-year gained. From a societal perspective, the incremental cost-effectiveness ratio was dominant. Conclusion: Transferability of a model-based UK-study in three steps proved to be an efficient method to provide an early indication of the cost-effectiveness of trastuzumab and has led to the provisional reimbursement of the treatment. http://repub.eur.nl/res/pub/28010/ 2010-03-20T00:00:00Z http://repub.eur.nl/res/pub/32580/ 2009-08-13T00:00:00Z BACKGROUND: The association of isolated tumor cells and micrometastases in regional lymph nodes with the clinical outcome of breast cancer is unclear. METHODS: We identified all patients in the Netherlands who underwent a sentinel-node biopsy for breast cancer before 2006 and had breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in the regional lymph nodes. Patients with node-negative disease were randomly selected from the years 2000 and 2001. The primary end point was disease-free survival. RESULTS: We identified 856 patients with node-negative disease who had not received systemic adjuvant therapy (the node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (the node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (the nodepositive, adjuvant-therapy cohort). The median follow-up was 5.1 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95% confidence interval [CI], 1.15 to 1.94); among patients with micrometastases, the adjusted hazard ratio was 1.56 (95% CI, 1.15 to 2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95% CI, 0.45 to 0.73) in the node-positive, adjuvant-therapy cohort, as compared with the node-positive, no-adjuvant-therapy cohort. CONCLUSIONS: Isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. In patients with isolated tumor cells or micrometastases who received adjuvant therapy, disease-free survival was improved. Copyright http://repub.eur.nl/res/pub/30357/ 2008-12-24T00:00:00Z Background: Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective follow-up study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence free survival. Methods: Two sample sets of high-risk primary breast cancer patients participating in a randomised national trial investigating the effectiveness of high-dose chemotherapy were analysed. Sera in set I (n = 63) were analysed by surface enhanced laser desorption ionisation time-of-flight mass spectrometry (SELDI-TOF MS) for biomarker finding. Initial results were validated by analysis of sample set II (n = 371), using one-dimensional gel-electrophoresis. Results: In sample set I, the expression of a peak at mass-to-charge ratio 9198 (relative intensity ≤ 20 or > 20), identified as haptoglobin (Hp) alpha-1 chain, was strongly associated with recurrence free survival (global Log-rank test; p = 0.0014). Haptoglobin is present in three distinct phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2), of which only individuals with phenotype Hp 1-1 or Hp 2-1 express the haptoglobin alpha-1 chain. As the expression of the haptoglobin alpha-1 chain, determined by SELDI-TOF MS, corresponds to the phenotype, initial results were validated by haptoglobin phenotyping of the independent sample set II by native one-dimensional gel-electrophoresis. With the Hp 1-1 phenotype as the reference category, the univariate hazard ratio for recurrence was 0.87 (95% CI: 0.56 - 1.34, p = 0.5221) and 1.03 (95% CI: 0.65 - 1.64, p = 0.8966) for the Hp 2-1 and Hp 2-2 phenotypes, respectively, in sample set II. Conclusion: In contrast to our initial results, the haptoglobin phenotype was not identified as a predictor of recurrence free survival in high-risk primary breast cancer in our validation set. Our initial observation in the discovery set was probably the result of a type I error (i.e. false positive). This study illustrates the importance of validation in obtaining the true clinical applicability of a potential biomarker. http://repub.eur.nl/res/pub/35525/ 2007-03-21T00:00:00Z Background: Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non - small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. Methods: Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan - Meier analyses from time of randomization. Results: Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. Conclusion: In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiotherapy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.