Research
The Cancer Epidemiology Unit of the Netherlands Cancer Institute has developed two research lines.
The first research line focuses on the etiology of hormone related female cancers (cancers of the breast, ovary and endometrium). Exposures of interest include exogenous hormones (oral contraceptives, hormone replacement therapy, and recently the long-term cancer risks of subfertility treatment have been placed high on the research agenda) and life style factors that influence endogenous hormone levels, such as physical activity. Special interest is also in the assessment of gene-environment interactions in hereditary breast/ovarian cancer families.
The second research line is focusing on the long term health consequences of the treatment of cancer with radiation, chemotherapy and hormonal treatment (tamoxifen), particularly in terms of the risk of developing a second cancer or cardiac disease.
Population based case control studies and cohort studies are conducted combining epidemiologic methods with molecular analyses, to differentiate risk factors for cancer according to specific genetic alterations in the tumor.
Late effects of cancer treatment
Now that curative treatment is available for a substantial group of cancer patients, it is increasingly important to evaluate how the occurrence of late complications of treatment affects their long term survival. The malignancies for which the survival benefits from modern treatment have been greatest occur at relatively young ages (Hodgkin's lymphoma), testicular cancer, several pediatric malignancies). This implies that the patients concerned, when cured, are subject to the full spectrum of early and late side effects, including complications emerging only several decades after initial treatment. Research in the 1980s clearly demonstrated that radiotherapy increases the risk of various new (second) primary malignancies, while some types of chemotherapy increase the risk of leukemia. The Epidemiology group started research in this area in the late 1980s and extended the outcomes of interest recently to treatment-related cardiovascular disease. Although there are several reports on radiation- and chemotherapy-associated excess mortality of cardiovascular disease, the incidence of cardiovascular disease has been rarely examined in late effects studies. Data on cardiovascular disease morbidity are much harder to obtain than information on second cancers, and, in addition, most countries have no population-based incidence data to compare with. Since such data are available in the Netherlands (for myocardial infarction, angina pectoris, congestive heart failure and cerebrovascular disease), we were in a good position to initiate research in this field.
The specific aims of ongoing studies are
- to evaluate the long-term treatment-specific risks of second cancers following Hodgkin's lymphoma, breast cancer, testicular cancer and childhood malignancies over a period of up to 30–35 years;
- to similarly evaluate the risk of cardiovascular disease;
- to examine the separate and combined effects of radiation dose, chemotherapy regimen, premature menopause and genetic factors on the risk of breast cancer after Hodgkin's lymphoma;
- to examine the effects of tamoxifen on the risk and prognosis of endometrial cancer after breast cancer;
- to examine whether cancer susceptibility genes contribute to the development of radiation-induced breast cancer;
- to study whether radiation-induced breast cancers are characterized by specific genomic aberrations;
- to investigate risk factors for the development and prognosis of contralateral breast cancer;
- to assess second malignancy risk in a nationwide historic cohort of 900 retinoblastoma patients born since 1945 (collaborative Dutch Cancer Society project with the Dept. of Ophtalmology of the Free University, Amsterdam);
- to evaluate a reproductive potential and premature menopause in female survivors of childhood cancer (joint project with Depts. of Pediatric Oncology and Gynecology of the Free University Amsterdam.
The study design consists of retrospective cohort studies, which are used as a sampling frame for nested case control studies for outcomes of interest. Recently, special focus is on the identification of genotypes associated with a stronger increase of radiation-induced cancer (collaboration with LJ van ‘t Veer, Molecular Pathology).
Key publications
Van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MWJ, Ribot JG, Hoekstra HJ, Ouwens GM, Aleman BMP, van Leeuwen FE. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol. [In press].
Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van 't Veer MB, Baaijens MH, de Boer JP, Hart AA, Klokman WJ, Kuenen MA, Ouwens GM, Bartelink H, van Leeuwen FE. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 2007; 109(5):1878-86.
Broeks A, Braaf LM, Huseinovic A, Nooijen A, Urbanus J, Hogervorst FB, Schmidt MK, Klijn JG, Russell NS, van Leeuwen FE, van 't Veer LJ. Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study. Breast Cancer Res 2007; 9(2):R26.
Cardous-Ubbink MC, Heinen RC, Bakker PJ, van den Berg H, Oldenburger F, Caron HN, Voute PA, van Leeuwen FE. Risk of second malignancies in long-term survivors of childhood cancer. Eur J Cancer 2007; 43(2):351-62.
Geenen MM, Cardous-Ubbink MC, Kremer LC, van den Bos C, van der Pal HJ, Heinen RC, Jaspers MW, Koning CC, Oldenburger F, Langeveld NE, Hart AA, Bakker PJ, Caron HN, van Leeuwen FE. Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA 2007; 297(24):2705-15.
Hooning MJ, Botma A, Aleman BM, Baaijens MH, Bartelink H, Klijn JG, Taylor CW, van Leeuwen FE. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007; 99(5):365-75.
Monninkhof EM, Elias SG, Vlems FA, van der Tweel I, Schuit AJ, Voskuil DW, van Leeuwen FE; TFPAC. Physical activity and breast cancer: a systematic review. Epidemiology 2007; 18(1):137-57.
Schmidt MK, Tollenaar RA, de Kemp SR, Broeks A, Cornelisse CJ, Smit VT, Peterse JL, van Leeuwen FE, Van't Veer LJ. Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 2007; 25(1):64-9.
Van Erp EJ, Heintz AP, Helmerhorst TJ, Koster ME, van Leeuwen FE. Settlement effected for damages for victims of diethylstilbestrol (DES)[Article in Dutch]. Ned Tijdschr Geneeskd 2007; 151(21):1197-200.
Voskuil DW, Monninkhof EM, Elias SG, Vlems FA, van Leeuwen FE. Task Force Physical Activity and Cancer. Physical activity and endometrial cancer risk, a systematic review of current evidence. Cancer Epidemiol Biomarkers Prev 2007; 16(4):639-48.
More publications by Flora van Leeuwen can be found on PubMed.
Biographic sketch
Flora Elisabeth van Leeuwen was born in 1956 in Rotterdam, The Netherlands. In 1981 she graduated (cum laude) from the Wageningen Agricultural University (MSc in Human Nature). In the same year she became head of the Department of Tumor Documentation, Clinical Trials and Epidemiology of the Netherlands Cancer Institute in Amsterdam, with the specific task to start an Epidemiology Group in this institute. In 1982-1983 she was awarded a research training fellowship by the International Agency for Research on Cancer. This period was spent to obtain a MSc degree in epidemiology at the Department of Epidemiology of the School of Public Health of the University of Alabama in Birmingham, USA) (Head: Dr. P. Cole). In the period 1983-1986, the Epidemiology Group of the Netherlands Cancer Institute quickly expanded, and in 1986 she became head of a separate Subsection on Cancer Epidemiology. This group is currently concentrating on two principal research lines: the etiology of breast cancer, and the long-term health consequences of the treatment of cancer, particularly in terms of the risk of developing a second cancer.
In 1994 she obtained her PhD degree (cum laude) at the Vrije Universiteit in Amsterdam (Thesis: Second malignancies as a sequel to cancer treatment, Promotores: Prof. dr. J. Vandenbroucke, Prof. dr. H.M. Pinedo). In 1998 she obtained a Chair in Cancer Epidemiology at the Faculty of Medicine from the Vrije Universiteit in Amsterdam.
From 1989 onwards, she also serves as a consulting epidemiologist to the Comprehensive Cancer Center of Amsterdam.
Coworkers
Marieke De Bruin, Post-doc
Lisette Hoogendoorn, Post-doc
Ina Mulder, Post-doc
Marjanka Schmidt, Post-doc
Eric Vermeulen, Postdoc
Dorien Voskuil, Post doc
Mathilde Cardous-Ubbink, Graduate student
Maartje Hooning, Graduate student
Tamara Marees, Graduate student
Sandra van den Belt-Dusebout, Graduate student
Alina Vrieling, Graduate student
Willem Klokman, Senior statistical analyst
Thea Mooij, Statistical analyst
Gijs Besseling, Research assistant
Geri de Leeuw-Mantel, Research assistant
Wieke Heideman, Research assistant
Esther Janssen, Research assistant
Kiki Jeanson, Research assistant
Marianne Kuenen, Research assistant
Gabey Ouwens, Research assistant
Renate Udo, Research assistant
Yvonne Ruwaard, Office Manager