The treatment of advanced breast cancer

After the introduction of aminoglutethimide, the first aromatase inhibitor for the treatment of breast cancer before 30 years, the drug has reached this growing importance in the treatment of advanced breast cancer and are currently being evaluated in the adjuvant setting. The third-generation aromatase inhibitors and inactivators, particularly anastrozole, letrozole, exemestane, and all have a powerful biochemical activities, with 97-99% inhibition. InIn addition, these drugs are well tolerated, and clinical trials have demonstrated their superiority over conventional therapy drugs (aminoglutethimide and megestrol acetate), in second place.

The results of these drugs as first-line treatment are more varied. Letrozole was found to be superior in terms of overall response rate, time to progression (TTP) tamoxifen.

These inhibitors have been shown to be superior to tamoxifen alsoparticular subgroups, such as estrogen (ER) / progesterone receptor tumors (PgR)-positive and in patients not exposed to adjuvant endocrine therapy.

Anastrozole, a finding, on the other hand, the equivalent effectiveness in clinical trials with tamoxifen, but it is not clear whether it provides superior. Preliminary results of a trial being evaluated exemestane are encouraging, but so far the number of patients is too small to draw conclusions. The first results of thesenew compounds support the hypothesis that the clinical efficacy, the degree of suppression of estrogen, they produce is connected. The observation of in vitro studies that tumor cells can adapt to low estrogen levels indicates that therapeutic drugs may be deleted can be found as a potent estrogen. The observed lack of cross-resistance between aromatase inhibitors and inactivators (ex-steroidal aromatase inhibitors) is a central themefurther investigation.

Aromatase inhibitors suppress estrogen synthesis, blocking the final step in the synthesis of aromatization of androgens into estrogens. Although the enzyme aromatase is found in the ovaries and peripheral tissues (the place of the E1 synthesis in postmenopausal women) the same, the initial results found that blocking estrogen with ovarian gonadotropin aminoglutethimide has been canceled. This was also found for the second generation of aromataseinactivator formestane, so it was thought that these drugs are not suitable for the treatment of premenopausal women.

This remains to be demonstrated for the third-generation inhibitors / inactivators, in the light of their power can be much bigger, they will also block ovarian aromatase activity.

The synthesis routes of estrogen have been described in postmenopausal women and are not reported in detail. Briefly to point out that hiscirculating androgens (mainly androstenedione) synthesized in the adrenal glands, and (to a lesser extent) in the ovaries are estrogens in several peripheral tissues such as muscles, connective tissue, skin, liver and converted. estrogen synthesis occurs in normal breast tissue and breast tumors. Interestingly, unlike what is seen in subjects in pre-menopausal women, estradiol concentrations are significantly higher than the tissue concentrations in postmenopausalWomen. If this local synthesis of active absorption mechanisms are interconnected, or both, is not yet known.