Endocrine therapy tailored to individual breast cancer patients: developing tests to predict treatment outcome

Project leader: Dr. S.C. Linn, Medical Oncologist, Departments of Medical Oncology and Molecular Biology, Netherlands Cancer Institute – Antoni van Leeuwenhoek hospital, Amsterdam Abstract Breast cancer affects approximately 10,000 women per year in the Netherlands. Each year around 3,500 patients die of the disease. More than 40% of those patients is younger than 65 years of age (1).

Standard breast cancer treatment consists of surgery, if necessary completed with radiotherapy and chemotherapy and/ or endocrine therapy. Local radiotherapy is prescribed to reduce the risk of local recurrence, while systemic treatment (chemotherapy and endocrine therapy) is indicated to decrease the chance of distant metastases.

In the Netherlands, systemic treatment is advised to a patient if the absolute benefit (the percentage increase in chance to survive breast cancer for at least 10 years) is 5% or more (2). Only patients whose tumors express a hormone receptor (estrogen receptor and/ or progesterone receptor), and who have a substantial risk of disease recurrence, will be prescribed adjuvant hormonal therapy. Roughly 75% of all tumors express one or both hormone receptors. Most patients are already cured by surgery (with or without radiotherapy). Only half of the patients with micrometastases (metastases too small to detect with the current imaging techniques) benefit from endocrine therapy. As doctors lack predictive tests that guide them to select only those patients who will benefit from endocrine therapy, they tend to treat all patients who may benefit. Consequently, only one to two out of ten breast cancer patients are cured because of adjuvant tamoxifen therapy, while the others may only suffer from potential side effects without having any benefit.

In case of metastasized breast cancer, palliative treatment with tamoxifen is a good option. The chance of clinical benefit (reduction in tumor size and metastases or at least stabilization) for more than 6 months is in the order of 50%.

Clearly, a predictive test that guides doctors in the selection of only those patients who will benefit from tamoxifen treatment is urgently needed, as 80-90% of all adjuvant treated patients do not have any advantage from the therapy and approximately 50% of patients with metastastic breast cancer take this medicine in vain.

As a result of the unraveling of the human genome, in combination with the developments in information technology, it has become possible to generate millions of data points with relative little effort (3,4). With the help of, so-called, microarrays one can measure activity of about 23,000 genes in tissue (tumor and healthy tissue) in a single experiment. Given that a gene is coding for a hereditary characteristic, the activity of a single gene (c.q. the expression of a gene) can influence the behavior of a tumor. The combination of expressions of all genes together determines the characteristics of a tumor, e.g. treatment sensitivity, chance of local recurrence or distant metastases. The ultimate goal of this project is to develop, with the help of this and other techniques, a clinically useful predictive test for tamoxifen sensitivity. In this way the likelihood of tamoxifen treatment success may rise to 80-90% instead of 50%.

1. Visser O, Coebergh JWW, Dijck JAAM van, Siesling S (editors). Incidence of cancer in the Netherlands 1998. Utrecht: Vereniging van Integrale Kankercentra, 2002.
2. Richtlijn Behandeling van het mammacarcinoom 2005. Van Zuiden Communications B.V., Alphen aan den Rijn. ISBN 90-8523-101-9, blz 57-86.
3. Linn SC, van de Rijn M, Giaccone G. Toekomstige verfijning van diagnostiek en therapie met DNA-microarrays. I. Technologie en data-analyse. Ned Tijdschr Geneesk;147:795-799, 2003.
4. Linn SC, van de Rijn M, Giaccone G. Toekomstige verfijning van diagnostiek en therapie met DNA-microarrays. II. Toepassingen. Ned Tijdschr Geneesk;147:800-804, 2003.

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