In the year 2006 the multidisciplinary breast cancer research team was formally appointed by GROW organisation, as it is an important tumour type with a high tumour incidence and being the focus of research of many departments within the University Hospital Maastricht and University Maastricht.
The breast cancer research group will focus on 5 different research topics, that is, 1) follow-up strategies, 2) breast imaging studies, 3) treatment evaluations, 4) isolated tumour cells and micro metastases, and 5) prognostic and predictive marker studies.
1) Follow-up strategies
In June 2005 a multicentre trial was started, with patients being randomized into one of four arms: 1) follow-up as usual, which means four outpatient clinic visits in the first year and in two visits in the second year, with a yearly mammography; 2) outpatient clinic follow-up visits once a year with a mammography in combination with telephone interviews by a nurse-practitioner (NP) at the same time points as usual follow-up; 3) similar to arm 1, combined with a group intervention aimed at education, an Info-Care-Program (ICP); 4) similar to arm 2, combined with an ICP. The aim of this study is to investigate the cost-effectiveness of different follow-up strategies in curatively treated breast cancer patients. In total we will include 320 breast cancer patients. The primary endpoint of this study is QoL at 12 months after treatment.
Since the start of the study in 2005, 172 patients have been included, of which 121 in 2006. Both nurse practitioners and patients report encouraging experiences with the telephone follow-up. Also, the Info-Care-Programme has been well-received by patients (average mark 8 out of 10). There are only a few drop-outs (<5%) and at the moment 96% of questionnaires and 92% of cost-diaries have been returned. To conclude, the trial has been well-received on both national and international conferences and two manuscripts have been accepted for publication in international journals.
This project is entitled ‘Improving the efficiency and quality of follow-up after curative treatment for breast cancer', coordinated by dr. L. Boersma (Maastro Clinic), and supported by ZonMW for the time period 2005-2008.
2) Breast imaging studies
There has been a marked increase in demand for radiologic services which has not been met by commensurate increase in radiologist staffing. A possible solution to this problem is the concept of ‘skill mixing', in which trained radiologic technicians are used to perform duties previously reserved to radiologists. This project will assess the effectiveness of training specialised breast technicians, who are involved in the performance and interpretation of diagnostic mammograms in daily clinical practice. Technicians are trained in the pre-screening of mammograms, in which they distinguish patients with fully normal test results from cases with any abnormality. As the radiologist can then devote his attention mainly to the cases thought to be abnormal, time and costs can be saved, leading to a gain in quality and efficiency of diagnostic breast imaging. In the study, the costs and effects of this innovative strategy are compared to the current routine process of breast imaging.
This project is entitled ‘Performance of specialised breast technicians in diagnostic breast imaging (PERSPECT study)', coordinated by dr. K. Flobbe (dept. Radiology azM/UM), and supported by ZonMW for the time period 2005-2007.
The routine diagnostic work up in patients suspected with breast disease consists of clinical examination, mammography and ultrasonography when indicated. The increasing use of additional ultrasonography in these patients without a scientific basis has led to questions about the appropriateness and efficiency of its application. In a prior, large prospective study (MAMMOED-1 study) subgroups of patients were identified who benefit most from additional ultrasonography and subgroups in whom it does not yield additional diagnostic information. Based on these data, evidence-based guidelines were designed for appropriate application of breast ultrasonography, The current study concerns the further development of these guidelines, as well as the development of these guidelines, as well as the development of cost-effective implementation strategies, by means of an implementation study in a multicentre radiological setting.
Furthermore, on behalf of outcome evaluation of the implementation study, performance indicators are developed which can be used for quality assurance in diagnostic breast imaging.
This project is entitled ‘Implementation of evidence-based guidelines for appropriate use of ultrasonography in diagnostic breast imaging (MAMMOED-2 study)', coordinated by dr. K. Flobbe (dept. Radiology azM/UM), and supported by ZonMW for the time period 2004-2007.
3) Treatment evaluations
Two projects on surgery are funded by ZonMW.
Fast track surgery: with optimal use of modern peri-operative techniques the physical and psychological impact of surgery is minimised, resulting in a shorter recovery period after surgery. After a successful breast cancer surgery fast track program in the University Hospital Maastricht, this is now a project in cooperation with four other Dutch hospitals.
A next project concerns the development of a shortened recovery program to reduce the hospital stay.
According to current guidelines, postmenopausal women with a hormone sensitive breast tumour and an indication for adjuvant endocrine treatment, may be treated with 2-3 years tamoxifen, subsequently switching to an aromatase inhibitor for another 2-3 years. At the moment it is not known whether a total endocrine treatment duration of 5 years is optimal. In the DATA study, patients on treatment with tamoxifen, will be randomized between 3 or 6 years of subsequent treatment with an aromatase inhibitor (anastrozole). Primary endpoint is the 5-year disease-free survival. The required number of patients is 1900. The DATA study is a national study within the framework of the BOOG (borstkanker onderzoeksgroep Nederland) and has received central approval on December 21, 2006, with 31 centres open for inclusion at the end of 2006. By the first of January 2007, 82 patients were included.
This national BOOG study is entitled ‘A prospective randomised, open, multicentre, phase III study to assess different Durations of Anastrozole therapy after 2 to 3 years Tamoxifen as Adjuvant therapy in postmenopausal women with breast cancer (the DATA study)', coordinated by prof. dr. V.C.G. Tjan-Heijnen (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by AstraZeneca for the time period 2006-2015.
Patients with newly diagnosed large resectable (3 cm and above and/or lymph node positive) or locally advanced breast cancer will be randomly assigned to one of two treatment arms with neo-adjuvant chemotherapy. The study is designed to compare the efficacy and tolerability of neoadjuvant chemotherapy with AC followed by T (adriamycine, cyclophosphamide, taxotere) versus TAC (with upfront T) in 200 breast cancer patients. The primary endpoint is the pathologic complete response (pCR) rate to neoadjuvant chemotherapy at surgery. Secondary endpoints are the delivered chemotherapy dose and dose-intensity, the tolerability, the clinical responses correlated to pathological responses, the value of breast MRI scanning in evaluating response as compared to clinical palpation, ultrasound techniques and histo-pathological outcome (optional side study), the false-negative rate of the sentinel node biopsy after neoadjuvant chemotherapy (optional side study), the disease-free (DFS) and overall survival (OS) after 3 and 5 years follow-up, the relation between pCR and DFS/OS, and the feasibility of the criteria for reporting pathological tumour response in surgical breast and axillary node resection specimens. The prognostic and predictive value of tumour- and molecular markers, including ER, PgR, c-erbB2, microarray and other tumour characteristic analyses, will be analysed in another optional side study.
This national BOOG study is entitled ‘Sequential vs upfront intensified neoadjuvant chemotherapy in patients with large resectable or locally advanced breast cancer (the INTENS study)', coordinated by prof. dr. V.C.G. Tjan-Heijnen (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by Sanofi Aventis and Amgen, for the time period 2006-2012.
4) Isolated tumour cells and micro metastases
In the multicentre VAZ 01122 study a cohort of breast cancer patients eligible to undergoing a sentinel lymph node procedure are being studied to address three main questions: 1. the impact of presence of isolated tumour cells or micro metastases in the sentinel lymph node(s) to predict metastatic involvement in the completion axillary lymph nodes; 2. differences between institutions in sentinel lymph node pathology protocols and the impact on performance of additional axillary lymph node dissection; 3. cost-effectiveness of performing a sentinel lymph node procedure in breast cancer. A total of 540 eligible patients have been included, and have already resulted in 3 publications in the Annals of Oncology and the Annals of Surgical Oncology.
This multicentre study is entitled ‘VAZ-DO 2001-122: Changes in diagnostics and therapy in breast cancer due to introduction of the sentinel lymph node procedure', coordinated by prof. dr. V.C.G. Tjan-Heijnen (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by CvZ, for the time period 2002-2008.
The MIRROR study is a national cohort study, to determine the prognostic relevance of isolated tumour cells and micrometastases in the axillary lymph nodes and the impact of adjuvant systemic therapy on prognosis, as at present there is worldwide no consensus on whether to systemically treat or not to treat and look for these small tumour involvements. Primary endpoint is 5-years disease free survival. The cost-effectiveness of delivering adjuvant systemic therapy is another primary endpoint. Patients who underwent a sentinel lymph node procedure in 2005 or before and who have favourable primary tumour characteristics are eligible. In total 3000 patients will be included: one cohort without lymph node metastases and without adjuvant systemic therapy; one cohort with micro metastases and/or isolated tumour cells without adjuvant systemic therapy; and one cohort with micro metastases and/or isolated tumour cells with adjuvant systemic therapy. The patient selection is based on data of the comprehensive cancer centres (IKCs). Information on therapy and follow-up will be collected by the registration managers of the IKCs. Central pathology revision is performed by two pathologists. Several side studies will be performed.
This national BOOG study is entitled ‘Micrometastases and Isolated tumour cells: Relevant and Robust Or Rubbish, the MIRROR study in breast cancer', coordinated by prof. dr. V.C.G. Tjan-Heijnen (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by ZonMW, for the time period 2006-2009.
5) prognostic and predictive marker studies
To study the prognostic and predictive impact of different tumour markers and to obtain insight in different molecular pathways, research has been done and will continue in co-operation with the Radboud University Nijmegen (prof. dr. C.G.J. Sweep, prof. dr. R. Holland and prof. dr. A. Verbeek), and new liaisons have been initiated within the azM/UM with the research groups of prof. A.W. Griffioen, prof. dr. A. De Bruïne and dr. M. van Engeland.
In a prospective local study in 45 newly diagnosed breast cancer patients, the genetic changes at the tumour cell level caused by cox-2 inhibition, are being studied. At present, 23 patients have been included.
This study is entitled ‘cDNA micro-array analysis in human breast cancers before and after treatment with COX-2 inhibitor celecoxib: the development of predictive factors', coordinated by Dr. P.S.G.J. Hupperets (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by Pfizer, azM, FHLM, for the time period 2001-2008.
Selected publications
Hupperets PS, Tjan-Heijnen VC.
Primary or secondary G-CSF prophylaxis to support TAC chemotherapy in Breast Cancer. Ann Oncol 2006; 17:1181-1183
Foekens JA, Atkins D, Zhang Y, Sweep CGJ, Harbeck N, Paradiso A, Cufer T, Siewerts A, Talantov D, Span PN, Tjan-Heijnen VCG, Zito A, Specht K, Hoefler H, Golouh R, Schittulli F, Schmitt M, Beex LVAM, Klijn JGM and Wang X.
Multi-center validation of a gene expression based prognostic signature in lymph node-negative primary breast cancer.
J Clin Oncol, 2006; 24: 1665-1671
Span PN, Tjan-Heijnen VCG, Heuvel JJTM, de Kok JB, Foekens JA. Sweep CGJ.
Do the surviving (BIRC5) splice variants modulate or add to the prognostic value of total surviving in breast cancer?
Clinical Chemistry, 2007; 52: 1693-1700
Funding started in 2006
In vitro functional assays to assess pathogennicity of genetic variants in the breast cancer genes BRCA1 and BRCA2, coordinated by dr. E.B. Gómez García, Dr. M.R. Block (dept. of Clinical Genetics, azM/UM), funded by Science and Technology Foundation (Portugal)
Identification of pathogenic BRCA1 and BRCA2 sequence variants by gene-expression profiling, coordinated by dr. E.B. Gómez García, Dr. M.R. Block (dept. of Clinical Genetics, azM/UM), funded by Calouste Gulbenkian Foundation (Portugal)
A prospective randomised, open, multicentre, phase III study to assess different Durations of Anastrozole therapy after 2 to 3 years Tamoxifen as Adjuvant therapy in postmenopausal women with breast cancer (the DATA study)', coordinated by prof. dr. V.C.G. Tjan-Heijnen (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by AstraZeneca for the time period 2006-2015.
Sequential vs upfront intensified neoadjuvant chemotherapy in patients with large resectable or locally advanced breast cancer (the INTENS study)', coordinated by prof. dr. V.C.G. Tjan-Heijnen (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by Sanofi Aventis and Amgen, for the time period 2006-2012.
Micrometastases and Isolated tumour cells: Relevant and Robust Or Rubbish, the MIRROR study in breast cancer', coordinated by prof. dr. V.C.G. Tjan-Heijnen (div. Medical Oncology, dept. Internal Medicine, azM/UM), and supported by ZonMW, for the time period 2006-2009.
Research group
Prof.dr. V.C.G. Tjan-Heijnen, project leader
Dr. R. Beets-Tan
Dr. L. Boersma
Prof.dr. J.M.A. van Engelshoven
Dr. K. Flobbe
Dr. E.B. Gómez Garcia
Dr. P.S.G.J. Hupperets
Prof.dr. M.F. von Meyenfeldt
PhD students
M. de Boer
M. Bolster (Nijmegen)
P. Bult (Nijmegen)
M.L. Kimman
L. Vercauteren
B. Vriens