Louk Beex

• Radboud University Medical Centre (Radboudumc)

Background: Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Material and methods: Analo...

Breast cancer is the most common malignancy amongst women in the developed world. For patients with hormone-sensitive breast cancer eligible for adjuvant hormonal therapy, it is important to know if the ovaries are (still) functional or not. Indeed, the choice for a specific adjuvant hormonal treatment depends on the menopausal status of an individ...

This study aimed to evaluate self-reported cognitive functioning of postmenopausal breast cancer patients before and during endocrine treatment compared with healthy female controls, and to investigate associations between self-reported cognitive functioning, cognitive test performance and anxiety/depression, fatigue, and menopausal complaints. Sel...

This study aimed to identify medical and psychological predictors for cognitive performance of breast cancer (BC) patients before the start of adjuvant systemic treatment and to compare cognitive performance between BC patients and healthy controls adjusting for medical and psychological variables. 205 postmenopausal BC patients underwent pre-treat...

Several prospective studies into the effects of adjuvant systemic therapy on cognitive functioning suggest that a proportion of breast cancer patients show cognitive deficits already before the start of systemic therapy. Owing to, among others, methodological inconsistency, studies report different rates of this pre-treatment cognitive impairment....

To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC). Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients par...

De incidentie van schildkliercarcinoom is laag, jaarlijks rond 450 patiënten. Histopathologisch is bijna 90% van de schildkliercarcinomen een gedifferentieerde papillaire, folliculaire of folliculaire variant van een papillair carcinoom met een gemiddeld gunstige prognose. Het zelden en meestal op oudere leeftijd voorkomende ongedifferentieerde ana...

The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial investigates the efficacy and safety of adjuvant exemestane alone and in sequence after tamoxifen in postmenopausal women with hormone-sensitive early breast cancer. As there was a nationwide participation in The Netherlands, we studied the variations in patterns of care in the Compre...

We evaluated with long-term follow-up, the prognostic value of the mitotic activity index (MAI) and the volume corrected mitotic index (M/V-index) compared with that of the histological grade in breast cancer patients not treated with adjuvant systemic therapy. Of 739 consecutive patients living in the city of Nijmegen, the Netherlands, 477 patient...

#1133 Background Adjuvant hormonal therapies (HT) are frequently used in primary breast cancer (BC), yet few studies have examined their potential impact on cognition. Fundamental and human research indicate that estrogens play an important role in certain cognitive functions; therefore it is plausible that HT can affect cognition in BC patients (p...

Previous studies have indicated that a subset of cancer patients treated with chemotherapy show cognitive deficits and/or experience cognitive complaints, whereas literature about the influence of hormonal therapies on cognition is sparse. Because of the accumulating knowledge about the importance of estrogen for cognitive functioning, there is gro...

This phase III randomized open-label clinical trial was designed to evaluate the efficacy and safety of the steroidal aromatase inactivator exemestane versus the antiestrogen tamoxifen as first-line treatment for metastatic breast cancer (MBC) in postmenopausal women. The study was conducted at 81 centers and enrolled postmenopausal patients with m...

Dit artikel beschrijft mogelijkheden voor de interactie tussen huisartsen en het multidisciplinaire mammateam bij de preventie en diagnostiek van borstkanker en begeleiding tijdens en na behandeling van deze aandoening. De nadruk ligt op herkenning van risicogroepen, de mogelijkheden tot screening en mogelijke interventies bij veel voorkomende prob...

The most frequent ovarian malignancy in mature women is of epithelial origin. In children and adolescents, it is very rare, and in such cases it mostly concerns tumors of low malignant potential or low stage I tumors. We describe an 18-year-old girl presenting with umbilical metastasis as a first sign of an extremely aggressive stage IV ovarian ser...

In lymph-node-negative invasive breast cancer patients<55 years, the proliferation marker mitotic activity index (MAI) has previously been shown to be the strongest prognosticator. In studies without age definition, MAI was not strongly prognostic. We investigated the age dependency of the prognostic value of proliferation for distant metastasis-fr...

Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone res...

In this multi-institutional prospective study, we evaluated whether we could identify risk factors predictive for non-sentinel lymph node (non-SN) metastases in breast cancer patients with a positive sentinel lymph node (SN). In this multi-institutional study, 541 eligible breast cancer patients were included prospectively. The occurrence of non-SN...

We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an independent more diverse population of LNN patients from multiple institutions. Using custom-designed DNA chips we analyzed the expression of the 76 ge...

Natuurlijke of geïnduceerde uitval van de ovariële functie kan gepaard gaan met ernstige klachten.

Determine whether standard or high-dose chemotherapy leads to changes in fatigue, hemoglobin (Hb), mental health, muscle and joint pain, and menopausal status from pre- to post-treatment and to evaluate whether fatigue is associated with these factors in disease-free breast cancer patients. Eight hundred eighty-five patients were randomly assigned...

Post chemotherapy Granulocyte colony stimulating factor (G-CSF) reduces leucopenia, while G-CSF priming shortly before chemotherapy increases myelotoxicity. We performed a trial with a two-schedule crossover design to determine the optimal G-CSF schedule for densified 2-weekly chemotherapy. During 2-weekly chemotherapy days 1 and 2, G-CSF was given...

To validate the independent strong prognostic value of mitotic activity index (MAI) in lymph node (LN) -negative invasive breast cancer patients younger than 55 years in a nationwide multicenter prospective study. Analysis of routinely assessed MAI and other prognosticators in 516 patients (median follow-up, 118 months; range, 8 to 185 months), wit...

Women at risk of breast and ovarian cancer due to a genetic predisposition may opt for preventive surgery or surveillance. The aim of this study was to determine the effectiveness of surveillance in families with a BRCA mutation. Sixty-eight BRCA-families underwent surveillance using annual mammography, transvaginal ultrasound, and estimation of CA...

For many years, tamoxifen has been the 'gold standard' amongst anti-oestrogen therapies for breast cancer. However, the selective aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, have demonstrated advantages over tamoxifen as first-line treatments for advanced disease. Anastrozole is also more effective as an adjuvant treatment in...

The authors report a prospective study comparing magnetic resonance imaging (MRI) with mammography for screening in women having an estimated cumulative lifetime risk of breast cancer of at least 15% because of a familial or genetic predisposition. A clinical breast examination was done every 6 months and imaging studies (with independent readings)...

Results in previous qualitative studies of the association of the apoptosis inhibitor survivin with prognosis of breast cancer patients have been contradictory. Survivin mRNA was measured by quantitative TaqMan reverse transcription-PCR in 275 breast cancer tissues from patients with operable tumors and was correlated with established clinicopathol...

The vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and has proven to be of prognostic value in patients with primary breast cancer. In this study we investigated whether VEGF is of predictive value with regard to the efficacy of adjuvant systemic therapy in primary invasive breast cancer. In 1127 tumors of patients with inv...

Background: The ability of a solid tumor to grow and metastasize has a significant dependence on protease systems, such as the plasminogen activation system. The plasminogen activation system includes the urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1), among other molecules. Both uPA and PAI-1 are est...

There is limited knowledge of risk factors for breast cancer recurrence within 2 years. This study aimed to predict early failure and identify high-risk patients for prognostic and therapeutic purposes. We studied 739 patients from a randomized trial who were <56 years of age and had >/=4 or more positive lymph nodes, no distant metastases, and no...

The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging (MRI) with that of mammography for screening in this group of high-risk women. Women who had a cumulative lifetime risk of breast cancer of 15 percent o...

Tissue inhibitors of matrix metalloproteinase (TIMPs) may be involved in tumour growth, apoptosis, angiogenesis, invasion, and the development of metastases. This study has evaluated the association of the expression levels of the TIMP forms 1, 2, 3, and 4, measured by quantitative real-time RT-PCR, with classical clinicopathological characteristic...

It has been shown that urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-I) have predictive value for therapy success in advanced breast cancer. Levels of the complex between uPA and PAI-I, formed when both molecules are in their active form, might have superior predictive power. Here, we investigate the association between lev...

The tumor mRNA expression levels of mammaglobin, a novel breast-specific and breast cancer-associated marker, were correlated with disease outcome in 280 patients with primary breast cancer. Mammaglobin expression levels were assessed by quantitative reverse transcriptase polymerase chain reaction in frozen tumor tissue from breast cancer patients...

Guidelines are tools to improve the quality of care in daily practice. To accomplish adherence, active implementation is needed. The effect of audit, group-oriented feedback and educational activities to increase guideline adherence were investigated in this study. Treatment according to a guideline for premenopausal node-positive breast cancer pat...

One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system. This system comprises of, among others, the urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1). In this study we investigated whether the uPA:PAI-1 complex is associated with...

Vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and is up-regulated under hypoxic conditions. Hypoxic tumors are known to exhibit resistance to radiotherapy. We investigated the association between VEGF levels in tumor tissue and the effect of radiotherapy for relapse-free survival (RFS) and overall survival (OS) in node-neg...

Ductal carcinoma in situ (DCIS) of the breast is diagnosed more and more often in the Netherlands as a result of mammographic population screening and improved mammography techniques. Mastectomy and local excision, with or without radiotherapy, are used for the treatment of DCIS, but breast-conserving therapy seems a logical option in view of the f...

Vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and is associated with a poor prognosis in patients with primary breast carcinoma. In the current study, the authors investigated whether there was an association between VEGF levels in tumor tissues and response rates to first-line, systemic therapy in patients with advanced b...

In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-1 for relapse-free survival (RFS) and MF...

Women with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. Patients with measurable disease were eligible if they had receive...

Recently, cyclin-E was reported to be the most prominent prognostic factor for breast cancer outcome described so far, even surpassing axillary nodal involvement. Earlier studies on the prognostic value of cyclin-E in breast cancer, however, yielded heterogeneous results. Therefore, we set out to confirm and extend these results by quantitative Taq...

The use of high-dose adjuvant chemotherapy for high-risk primary breast cancer is controversial. We studied its efficacy in patients with 4 to 9 or 10 or more tumor-positive axillary lymph nodes. Patients younger than 56 years of age who had undergone surgery for breast cancer and who had no distant metastases were eligible if they had at least fou...

The beta-subunit of human chorionic gonadotropin (hCG) is encoded by four genes, of which expression of the hCGbeta-3, -5, and -8 genes could have prognostic value in breast cancer. Applying a new, modified Molecular Beacon reverse transcription-PCR assay, we investigated the prognostic value of the hCGbeta-3, -5, and -8 gene transcripts in 129 spo...

Here, we set out to assess CA9 expression levels by real-time quantitative RT-PCR in breast cancer tissue samples obtained from 253 patients, and correlated those with relapse-free (RFS) survival. The median follow-up time was 75 months (range 2-168 months). CA9 expression was mainly found in high-grade, steroid receptor negative cancer tissues. CA...

The recently described reversion-inducing cysteine-rich protein with Kazal motifs (RECK) inhibits membrane Type 1 matrix metalloproteinase (MMP-14), MMP-2, and MMP-9 secretion and enzymatic activity. Its expression is essential for normal vasculogenesis. Down-regulation of RECK has been implicated in tumor angiogenesis and progression. The authors...

Serum CA125 concentrations measured before and during chemotherapy may provide additional information for prognostic assessment of patients with epithelial ovarian cancer (EOC), and enable discrimination between patients who are likely to benefit from further therapy and those who will not. Medical records of 40 patients with advanced EOC, treated...

30 patients with advanced ovarian cancer, all platinum pretreated, were treated with an induction cycle of fotemustine. Maintenance therapy was given to 6 patients. No objective response was observed among the 21 evaluable patients. The main toxicities were gastrointestinal, with grade 3 nausea and vomiting reported in 40% of the patients, and haem...

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment fail...

Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advant...

E1AF is a transcription factor involved in regulation of several metastasis-associated genes, and is associated with overexpression of HER2/neu. We were unable to find a clear prognostic value of E1AF expression in human breast cancer. Furthermore, no association of E1AF levels with HER2/neu mRNA levels, hormone receptor status, histological grade,...

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment fail...

Women with a hereditary predisposition for breast cancer have an extremely high risk of developing invasive breast carcinoma, and many women consider prophylactic mastectomy to avoid this risk. The use of prophylactic mastectomy is still debated. Identification of frequent premalignant lesions in mastectomy specimens would support the preventive co...

At the St Gallen meeting of 2001 it was agreed to select high-risk patients for adjuvant systemic therapy by lymph node status, tumor size, age, hormone receptor status, and histological grade. In The Netherlands it was chosen to use either the histological grade or the mitotic activity index (MAI). The aim of this study was to retrospectively eval...

The transcription factor Ets-1 regulates the expression of several angiogenic and extracellular matrix remodeling factors, and might be implicated in disease progression of breast cancer. In the present study, the prognostic value of Ets-1 expression was assessed by quantitative real-time fluorescence RT-PCR in 123 sporadic primary breast cancer sa...

Peripheral neuropathy is a rare complication of the commonly used cytotoxic drug 5-fluorouracil (5-FU). We report a case of 5-FU-induced peripheral neuropathy in a patient with metastatic colorectal carcinoma. Discontinuation of 5-FU therapy is recommended in case of 5-FU-related neurotoxicity.

The growth and metastasising capacity of solid tumours are dependent on angiogenesis. Vascular endothelial growth factor is a mediator of angiogenesis. In this study we investigated whether vascular endothelial growth factor is associated with the natural course of the disease in primary invasive breast cancer. In 574 tumours of patients with node-...

We performed a phase I study of polyethylene glycol (pegylated, Stealth) liposomal doxorubicin (Caelyx, Doxil) using a prolonged (6-week) dose interval to reduce the incidence of skin toxicity that was dose-limiting at more conventional dose intervals, and which appeared to be schedule dependent. Eligible for the study were metastatic breast cancer...

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patient...

The optimal age boundaries for breast cancer screening are still under debate. A case-referent design was used to describe the effect of mammographic screening on breast cancer mortality along the continuum of age, based on a 20 year follow up period. The population based breast cancer screening programme in Nijmegen, The Netherlands, which has bie...

Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by membe...

Information on treatment outcome outside clinical trials is sparse. This is the first study that relates surgical and medical quality of care in daily practice with outcome. In a previous study we showed, that the quality of chemotherapy as described by a guideline and given in daily practice to premenopausal primary breast cancer patients was subo...

Sentinel lymph node (SN) biopsy will increasingly replace axillary lymph node dissection (ALND) for staging in breast cancer. For daily practice, examination of the SN by serial sectioning (SS) and/or immunohistochemistry (IHC) is being promoted. Use of these techniques may result into stage migration due to the increased detection of micro-metasta...

Although breast cancer screening is recommended to start at a younger age for women with a hereditary risk of breast cancer, the sensitivity of mammography for these women is reduced. We compared magnetic resonance imaging (MRI) with mammography to determine which is more sensitive and whether MRI could play a role in the early detection of breast...

Age-standardised breast cancer mortality rates have been stable for decades. However, rates have started to decline in several Western countries. In countries where population-based screening programmes for breast cancer were introduced in the late 1980s or early 1990s, the key question now is to what extent screening is responsible for the reporte...

Age-standardised breast cancer mortality rates have been stable for decades. However, rates have started to decline in several Western countries. In countries where population-based screening programmes for breast cancer were introduced in the late 1980s or early 1990s, the key question now is to what extent screening is responsible for the reporte...

Tamoxifen has been used for the systemic treatment of patients with breast cancer for nearly three decades. Treatment success is primarily dependent on the presence of the estrogen receptor (ER) in the breast carcinoma. While about half of patients with advanced ER-positive disease immediately fail to respond to tamoxifen, in the responding patient...

Lymph node status is the most important factor to select high-risk breast cancer patients for adjuvant systemic therapy. For node-negative breast cancer, it is recommended to select patients by tumor size, estrogen and/or progesterone receptor status, age and histological grade. It has been advocated to replace histological grade by the mitotic act...

Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicente...

Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing ho...

There is an abundance of evidence that adjuvant systemic therapy with chemotherapy or endocrine therapy results in better survival for all patients with resectable breast cancer. The absolute 10-year survival advantage however varies for the different patient groups. Therefore, for each individual patient the choice of adjuvant therapy must take in...

Liarozole is an imidazole compound that inhibits enzymes involved in steroid hormone aromatisation and retinoid metabolism. The IDBBC branch of the EORTC has performed a series of phase II studies of the agent in four groups of postmenopausal women with metastatic breast cancer. This paper reports the results of the first two groups: 'Chemotherapy...

The aim of this study was to investigate the clinical activity and toxicity of a modified PVB regimen (cisplatin, vinblastine and bleomycin) in patients with advanced or recurrent, pure granulosa cell tumours (GCTs) or mixed granulosa-theca cell tumours (GTCTs). The PVB regimen consisted of cisplatin (P) 20 mg/m2 intravenous (i.v.) days 1-5, vinbla...

The quality of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and the compliance with guidelines for this treatment were studied in 323 premenopausal patients with node positive breast cancer, who were treated in the Comprehensive Cancer Centre East of The Netherlands (IKO) from 1988 to 1992, outside the setting...

This paper outlines the changes which have occurred over the last 25 years in the methods employed for the measurement of oestrogen receptors to aid the management of women with breast cancer. Immunohistochemistry is now the method of choice and knowledge of oestrogen receptor status is being used with increasing frequency for the selection of adju...