Fulvestrant: Neue Therapieoption beim hormonsensiblen, fortgeschrittenen Mammakarzinom

Zusammenfassung

Fulvestrant stellt neben den herkömmlichen endokrinen Substanzgruppen wie den SERMs, den Aromatasehemmern und den Gestagenen eine weitere Therapieoption beim hormonsensiblen, metastasierten Mammakarzinom in der Postmenopause dar.

Bei Fulvestrant handelt es sich um den ersten Vertreter einer Klasse von Östrogenrezeptorantagonisten ohne östrogenagonistische Restkomponente, der zu einer Degradation und Down-Regulation des Östrogenrezeptors führt. Aus präklinischen In-vitro- und In-vivo-Untersuchungen ist neben einer stark antiproliferierten Aktivität eine hohe Effektivität nach Tamoxifenresistenz bei fehlendem Östrogenagonismus am Endometrium von Fulvestrant bekannt. Internationale Phase-III-Studien belegen mindestens equivalente Wirksamkeit von Fulvestrant im direkten Vergleich zum Anastrozol in der Second-line-Therapie des metastasierten Mammakarzinoms. Ein direkter Vergleich zum Tamoxifen in der First-line-Therapie konnte hingegen nur für östrogenrezeptor- und progesteronrezeptorpositive Karzinome einen Vorteil zugunsten des Fulvestrant zeigen. Ein klinischer Benefit von 40 bis 60 % kann sowohl mit Fulvestrant nach stark vorbehandelten Patientinnenkollektiven erreicht werden als auch mit herkömmlichen endokrinen Therapien nach vorheriger Fulvestranttherapie. Nach der kürzlichen Zulassung von Fulvestrant für die Second-line-Therapie nach Antiöstrogentherapie beim postmenopausalen, hormonsensiblen fortgeschrittenen Mammakarzinom stellt sich zunehmend die Frage der Positionierung in der endokrinen Kaskade. Bei einem standardisierten Einsatz der Aromatasehemmer in der First-line-Therapie des metastasierten Mammakarzinoms und ihrer zunehmenden Bedeutung auch für die adjuvante Therapie können sich weitere Verschiebungen in der Therapiesequenz ergeben. Davon und von einer Reihe laufender Studien mit der Beteiligung von Fulvestrant wird seine Positionierung abhängen.

Abstract

Endocrine therapy with agents that reduce estrogen levels or block the estrogen receptor remains an important motility in breast cancer management. Recently, a number of alternative endocrine treatments have been developed, including several selective estrogen receptor modulators (SERMs), aromatase inhibitors (AI) and most recently the “estrogen receptor downregulator” Fulvestrant. Fulvestrant is a new type of endocrine treatment, an estrogen receptor (ER) antagonist with no agonist effects. Fulvestrant down-regulates cellular levels of the ER, resulting in decreased expression of the progesterone receptor. Pre-clinical and early clinical data suggest a novel mode of action which may result in a different clinical profile from that of Tamoxifen and related compounds. In post-menopausal patients with hormone sensitive, advanced breast cancer the efficacy of Fulvestrant has been proven in phase III trials. These second line trials showed a comparable efficacy of Fulvestrant to that of the third generation aromatase inhibitor Anastrozol. A recently published first line comparison between Tamoxifen and Fulvestrant in hormone sensitive, metastatic breast cancer indicated that Fulvestrant only offered an advantage in ER and PR positive tumours. Fulvestrant has shown efficacy when used after progression after Tamoxifen or aromatase inhibitors have been administered in post-menopausal women with metastatic breast cancer. It is also known that subsequent endocrine treatments after progression with prior Fulvestrant administration demonstrated no cross resistance between Fulvestrant and other endocrine therapies. In summary, Fulvestrant represents an additional anti-estrogen for the treatment of post-menopausal women with advanced breast cancer. The place of Fulvestrant within the sequential endocrine cascade in metastatic breast cancer needs to be evaluated in future studies.

Mammakarzinom - Antiöstrogene - SERM - SERD - Fulvestrant

Breast cancer - anti-estrogens - SERM - SERD - Fulvestrant

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