Aromatase inhibition with 4-OHAndrostenedione after prior aromatase inhibition with aminoglutethimide in women with advanced breast cancer

Abstract

One hundred and twelve post menopausal or post oophorectomy women with advanced breast cancer (BC) who had all previously had aminoglutethimide (AG) were treated with the potent aromatase inhibitor 4-hydroxy androstenedione (4-OHA). Twenty three women (21%) had a partial response to 4-OHA while another twenty five patients (22%) had stabilization of previously progressing disease. Patients responded to 4-OHA both after previously responding to then relapsing on, and after failing to respond to aminoglutethimide. Toxicity was minimal. This study shows that potent aromatase inhibition with 4-OHA is effective in women with advanced BC who have already been treated with a less potent aromatase inhibitor, and suggests that relative changes in oestrogen levels may be more important than absolute levels.

Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

“…These efforts have followed the seminal study by Murray and Pitt showing that breast cancer patients previously treated with the first-generation nonsteroidal AI aminoglutethimide subsequently responded to 4-hydroxyandrostenedione [50]. In general, objective response rates with a second-line AI are not high (0%-26%), but clinical benefit (which includes stable disease of Ն6 months' duration) is observed in 20%- 62% of patients.…”

Aromatase inhibitors in breast cancer.

“…6 months (mo). References for these studies are (I) Murray & Pitt (1995); ( to formestane after failing aminoglutethimide (Murray & Pitt 1995), exemestane after failing anastrozole or letrozole (Lønning et al 2000) and, importantly, the observations of a durable stable disease in patients exposed to formestane after failing third generation compounds such as anastrozole and letrozole (Carlini et al 2001) suggest that there may be alternative explanations. Notably, treatments with exemestane as well as formestane by the oral route have been shown to suppress plasma sex hormone-binding globulin levels (Dowsett et al 1992, Johannessen et al 1997.…”

Cross-resistance to different aromatase inhibitors in breast cancer treatment.

“…Accordingly, when evaluating responses to treatment with a second aromatase inhibitor in patients failing on therapy with another aromatase inhibitor, the second aromatase inhibitor in general is administered as a third-line (or later) regimen. While the literature dealing with response rates to different forms of second-line endocrine therapy is substantial, there are few reports dealing with the response rates to third-line hormone therapy in large groups of patients (Garcia-Giralt et al 1992, Iveson et al 1993a, Murray & Pitt 1995. Although such data on this issue have to be interpreted carefully due to selection of patients, the general impression is that a substantial number of patients obtain stabilization of disease and a limited number achieve an objective response (complete response (CR)+ partial response (PR)) to third-line (or later) regimens.…”

“…Of these, four have evaluated use of a steroidal aromatase inhibitor following relapse on a non-steroidal agent, while one study evaluated use of a non-steroidal inhibitor following relapse on a steroidal drug. Two studies evaluated the use of formestane (250 mg every second week) in patients relapsing on aminoglutethimide (Murray & Pitt 1995, Geisler et al 1996a. One study evaluated use of exemestane administered as a 'high-dose regimen' of 200 mg daily in patients relapsing on aminoglutethimide (Thürlimann et al 1997), and one study has evaluated exemestane 25 mg daily in patients relapsing on either aminoglutethimide or novel aromatase inhibitors such as anastrozole, letrozole or vorozole (Lønning et al 1998).…”

“…The two studies evaluating use of formestane in patients progressing on aminoglutethimide revealed an objective response in 23/112 (21%) (Murray & Pitt 1995) and 3/30 (10%) (Geisler et al 1996a) patients respectively.…”