Successful Translation Research with Selective Oestrogen Receptor Modulators to Treat and Prevent Breast Cancer

Zusammenfassung

Vor 30 Jahren spielte die Antiöstrogentherapie mit Tamoxifen nur eine zweitrangige Rolle in der Mammakarzinomtherapie. Die Hoffnungen, die Heilung des metastasierten Mammakarzinoms erreichen zu können, fokusierten sich auf die Entwicklung neuer Zytostatika und der Hochdosischemotherapie mit Knochenmarktransplantation. Ähnliche Strategien wurden in der adjuvanten Behandlung des Mammakarzinoms verfolgt. Vereinfacht gesagt, das Ziel war es, die Krebszellen mit unspezifischen zytotoxischen Substanzen zu töten, während der Patient durch supportive Maßnahmen am Leben gehalten wurde. Aber die medizinische Forschung verläuft nicht nur gradlinig und alternative Ansätze, die die Kontrolle des Tumorwachstums mit minimalen Nebenwirkungen erlauben, wurden entwickelt - die sogenannte targeted therapy. Die Elemente dieser neuen Strategien waren seit 20 Jahren gestützt durch die Ergebnisse der Grundlagenforschung etabliert. Der Ansatz der Langzeitantihormontherapie zur Kontrolle des Zellwachstums über „targeting“ des Tumor-Östrogenrezeptors hat die Behandlung des Mammakarzinoms revolutioniert. Der Erfolg dieser Strategie wird an der Abnahme der Mortalität des Mammakarzinoms abgelesen. Die translationale Forschung über den Tumor-Östrogenrezeptor mit einer ganzen Bandbreite neuer antiöstrogener Substanzen (Aromatasehemmer, reine Antiöstrogene) lässt neue Therapiemodelle der „targeted therapy“ prophezeien. Wenn man sich die Pharmakologie der „Antiestrogene“ genauer anschaut, wird man erstaunt sein. Die nicht steroidalen „Antiöstrogene“ sind selektive Östrogenmodulatoren (SERMs). Mit anderen Worten, die Substanzen wirken an der Mamma als Antiöstrogene, als Östrogene im Knochen und vermindern den Cholesterinspiegel. Dieses Wissen ermöglicht einen praktischen Ansatz in der Chemoprävention des Mammakarzinoms bei Frauen mit hohem Risiko (Tamoxifen) und niedrigem Risiko (Raloxifene).

Abstract

Thirty years ago, antiestrogen therapy with tamoxifen played only a secondary role in breast cancer care. All hopes to cure metastatic breast cancer were still pinned on either the discovery of new cytotoxic drugs or a dose dense combination of available cytotoxic drugs with bone marrow transplantation. A similar strategy with combination chemotherapy was employed as an adjuvant for primary breast cancer. Simply stated, the goal was to kill the cancer with nonspecific cytotoxic drugs while keeping the patient alive with supportive care. However, medical research does not travel in straight lines and alternative approaches emerged to solve the problem of controlling tumour growth with minimal side effects. The approach was targeted therapy. All the elements of the new strategy were in place twenty years ago supported by scientific principles derived from laboratory research. The approach of using long-term antihormone therapy to control early stage breast cancer growth would revolutionise cancer care by targeting the tumour oestrogen receptor (OER). The success of the strategy would be evidenced by lives saved and contribute to a decrease in the national mortality figures for breast cancer. More importantly, translational research that targeted the tumour OER with a range of new antioestrogenic drugs (aromatase inhibitors, pure antioestrogens) would presage the current fashion of blocking survival pathways for the tumour by developing novel targeted treatments. But a surprise was in store when the pharmacology of “antioestrogens” was studied in detail. The nonsteroidal “antioestrogens” are selective oestrogen modulators (SERMs). In other words, the compounds are antioestrogens in the breast, oestrogens in the bone and lower circulating cholesterol. This knowledge would establish a practical approach to breast cancer chemoprevention for both high risk (tamoxifen) and low risk (raloxifene) women.

Schlüsselwörter

Mammakarzinom - Prävention - Tamoxifen - SERM - DICS

Key words

breast cancer - prevention - tamoxifen - SERM - DICS

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