CLINICAL USE OF AROMATASE INHIBITORS IN THE TREATMENT OF ADVANCED BREAST-CANCER

The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour growth. After failure of tamoxifen - the standard ''first-line' ' hormonotherapy for advanced breast cancer (ABC) - the most frequentl y prescribed endocrine therapies are progestins and aromatase inhibito rs (AIs) (''second-line'' hormonotherapy). Estrogen deprivation throug h AIs provides effective treatment of hormone-dependent ABC in postmen opausal (PMP) women. Over the past few years, the goals of our researc h programme were to develop more potent, more selective and better tol erated AIs than our first AI, aminoglutethimide (AG). Lentaron(R) (4-h ydroxyandrostenedione, formestane), a highly selective steroidal compo und was the first of the new AIs to be used in clinical trials. It is a substrate analogue, administered as an i.m. injection every 2 weeks. It is effective in the treatment of ABC with an objective response ra te (ORR) similar to tamoxifen and megestrol acetate (IMA) and is gener ally web tolerated; rare instances of injection site reactions have be en reported. Afema(R) (fadrozole HCl), a non-steroidal AI is active or ally, and effectively suppresses estrogen levels in PIMP women, but it is not completely selective for aromatase when administered at higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day i t has an anti-tumour efficacy similar to MA, a good tolerability and n o clinically relevant effects on other hormones of the endocrine syste m. Letrozole is the fourth of our AIs in clinical development. It is a non-steroidal, achiral, orally active, potent and highly selective co mpetitive AT. Clinical endocrine studies have shown that the dose of 0 .5 mg a day is the lowest dose achieving maximum estrogen suppression. Over a wide dose range, a lack of clinically relevant effects on othe r hormones of the endocrine system has confirmed its high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who failed prev ious therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase IIb/III study has been completed and two others are ongoing, comparing two doses of letrozole with IMA or AG to confirm the anti-tumour effi cacy of letrozole in the treatment of ABC in PIMP women after treatmen t with anti-estrogens. Preliminary results from the completed trial sh ow that letrozole 2.5 mg is superior to 0.5 mg in terms of ORR, time t o progression and time to treatment failure, and is superior to the st andard dose of MA in terms of ORR and tolerability. Therefore letrozol e 2.5 mg can be recommended as a first choice for the treatment of PMP patients with hormone receptor-positive or unknown ABC after anti-est rogen therapy. (C) 1997 Elsevier Science Ltd.