Endocrine Adjuvant Therapy for Localized Breast Cancer
A partir des données de deux essais cliniques ayant inclus des patientes atteintes d'un cancer du sein avant la ménopause, cette étude compare l'efficacité, du point de vue du taux de survie sans maladie à 8 ans et du taux de récidive distante à 8 ans, et la toxicité de 3 traitements adjuvants, l'un à base de tamoxifène seul, l'autre à base de tamoxifène et d'une suppression de la fonction ovarienne, et le dernier à base d'exémestane et d'une supression de la fonction ovarienne
Investigators now report in the Journal the updated results of two critical trials of endocrine therapy in early-stage breast cancer — SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) — with overlapping groups that permitted a combined analysis. As in many other endocrine-therapy trials, the effects were not apparent in earlier analyses, but after 8 to 9 years of follow-up, the results are clear. In premenopausal women, the addition of ovarian suppression to tamoxifen was more effective in increasing disease-free survival than tamoxifen alone, and the addition of the aromatase inhibitor exemestane to ovarian suppression was even better than tamoxifen plus ovarian suppression, although at a cost of a longer list of adverse events. This finding held true across essentially all subgroups of patients, regardless of lymph-node status, chemotherapy status before the initiation of endocrine therapy, and age among premenopausal patients.
These data make sense. Since these trials were restricted to patients with tumors that were estrogen-receptor–positive, we would anticipate that the patients with the greatest reduction in estrogen levels would have the greatest benefit. The use of tamoxifen in premenopausal patients is clearly effective as a treatment for metastatic tumors and as adjuvant therapy, since it acts as an antiestrogen in breast cells. However, the drug increases ambient estrogen levels in other tissues (e.g., the uterus and bones). Because of the pharmacokinetic properties of tamoxifen, levels of the drug may build up in the blood, reaching several micromolars. Nonetheless, in a variety of experimental systems, a dose of estradiol at 1% of the dose of tamoxifen can reverse the inhibitory effects of tamoxifen and its metabolites. Thus, it is not surprising that blocking ovarian sources of estrogens could add to the effectiveness of tamoxifen.
In postmenopausal women, aromatase inhibition is more effective than tamoxifen as a treatment for metastatic tumors and as adjuvant therapy. Although the adrenal glands do not produce estradiol or estrone, adrenal androgens, which are made in large quantities by the adrenal cortex, can be aromatized to estrone and estradiol in many tissues, including fat, skin, liver, breast, and breast cancer. Since ovarian ablation in premenopausal women essentially renders them postmenopausal, it is not surprising that the addition of exemestane to ovarian suppression was superior to either tamoxifen alone or tamoxifen plus ovarian suppression, since exemestane can also prevent the production of estrogens by peripheral aromatization and provide even lower ambient estrogen levels. (In the SOFT and TEXT trials, ovarian suppression was achieved by the intramuscular injection of triptorelin every 28 days, by bilateral oophorectomy, or by ovarian irradiation.)
Even though the data from essentially all clinical trials are analyzed on an intention-to-treat basis, it seems worth pointing out that at least one quarter of the patients in the combined analyses in SOFT and TEXT discontinued treatment, mainly because of therapy-related side effects. The degree of such subjective side effects was clearly higher with ovarian suppression, a factor that has led many clinicians to reserve this treatment for patients whom they consider to be at highest risk. However, the benefits of ovarian suppression combined with either exemestane or tamoxifen were substantially the same in all categories of risk. It is unfortunate that the use of bone-strengthening agents (e.g., bisphosphonates) or inhibitors of receptor activator of nuclear factor-
κB ligand (RANKL) was not permitted in this trial unless such use was medically indicated, since it is now clear that such agents reduce skeletal events associated with aromatase inhibitors, reduce fracture recurrences, and increase overall survival.
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New England Journal of Medicine , éditorial en libre accès, 2017