Aromatase inhibitors: the journey from the state of the art to clinical open questions

Regarding patients with locally advanced and metastatic endocrine-responsive postmenopausal breast cancer, a meta-analysis of phase III randomized controlled trials comparing first-line endocrine therapy with third-generation AIs and TAM was reported in the literature. This study examined OS and addressed whether the progression-free survival (PFS) benefit of AI therapy results from a reduction in de novo resistance or a delay in acquired resistance to endocrine therapy. It included data from four large trials, all designed with TAM administered in the control arm and different AIs (exemestane, anastrozole, and letrozole) administered in the experimental arm. Every trial was reviewed for the clinical benefit rate, duration of clinical benefit (DoCB), PFS, and OS.

3. Androstenedione snugly fits in the active site cavity

Steroidogenic factor 1 (SF1), a transcription factor that is expressed in endometriotic tissue but absent in endometrium, is integral for the expression of STAR and aromatase. SF1, whose expression depends on the presence of prostaglandin E2 in endometriotic cells, assembles enhancer transcriptional complexes, which then bind to the promoters of STAR and aromatase genes to induce their expression (1, 11, 28, 29). Additionally, in normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factors that act on neighboring epithelial cells to induce the expression of the enzyme 17 beta-hydroxysteroid dehydrogenase type 2 (HSD17B2). This enzyme catalyzes the conversion of E2 to estrone, a less biologically-active estrogen.

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The more patients follow endocrine therapy, the more we can achieve longer and better responses. In summary, the results of this meta-analysis suggest that when AIs are initiated instead of TAM in premenopausal women, in addition to OFS, the absolute recurrence risk can be decreased by 3% at 5 and 10 years. In postmenopausal women, approximately 70% of all breast cancers are hormone receptor-responsive and candidates for endocrine therapy (35).

There have been several case reports published successfully using AIs in postmenopausal women with endometriosis (33, 55, 58–62). All patients had undergone either surgical or natural menopause, with several patients having been exposed to hormone replacement therapy. Most women were previously treated for endometriosis with either surgery, GnRH agonists, or progestins. A prospective randomized trial was done by Soysal et al. of 80 women to evaluate the efficacy of using either a combination of anastrazole and goserelin, or goserelin alone for six months, after conservative surgery for severe endometriosis (43). Patients were randomized to receive a combination of anastrazole 1 mg/day plus subcutaneous depot injections of 3.6mg goserelin every 4 weeks or goserelin plus a placebo tablet for the same amount of time. Patients were treated for 24 weeks and evaluated at 6, 12, 18, and 24 months after the end of medical treatment.

The aromatase inhibition activity in the enzymatic test for compounds 21 and 22 was 0.82 µM and 0.86 µM, respectively 22. A particularly interesting group from the point of view of organic synthesis and targeted drug design are non-steroidal aromatase inhibitors, also referred to as type II inhibitors. Molecules from this group bind non-covalently to the heme residue found in the aromatase enzyme. The consequence of this is the blocking of the possibility of androgens binding to the molecular target by saturating the site of its binding. Aromatase inhibition by non-steroidal inhibitors, unlike steroidal ones, is reversible due to competitive androgen inhibition 4,9. Non-steroidal aromatase inhibitors have two basic chemical elements in their structure.

This conclusion is further supported by the observation that mice null for the aromatase gene are more vulnerable to excitotoxic brain damage than wild-type animals 90. Given the prolong relapse prospect of hormone receptor-positive breast cancer, extended course of endocrine therapy has been evaluated in multiple clinical trials. Currently, extended therapy of tamoxifen beyond 5 years is still controversial. Although there appears to be some marginal benefit of extended tamoxifen, this is offset by its toxicities particularly increased risks of endometrial cancer and thromboembolism 59–61. In contrast, three large randomized clinical trials (ABCSG 6a 62, MA.17 63, NSABP B-33 64) have demonstrated that extending the duration of endocrine therapy with AIs after 5 years of tamoxifen can be beneficial.

2. Non-Steroidal Aromatase Inhibitors

AIs appear to be more effective than tamoxifen in ER-positive tumours regardless of PgR or growth factor receptor status (14,15). Aromatase inhibitors are the most effective medications today for treating or preventing the recurrence of estrogen-fueled breast cancers in post-menopausal women. Aromatase inhibitors are among the most effective medications today for treating or preventing the recurrence of estrogen-fueled breast cancers in post-menopausal women. Dubbed the star molecule of longevity (for its leading role in the ‘French Paradox’), the antioxidant resveratrol continues to fascinate scientists.

• Moreover, for the monotherapy comparison, 25.2% of patients receiving TAM selectively crossed over to letrozole, and 39.5% of patients receiving TAM selectively crossed over for the four-arm comparison.
• New natural product AIs may be clinically useful for treating postmenopausal breast cancer and may also act as chemopreventive agents for preventing secondary recurrence of breast cancer.
• The GC-MS method was used to measure 19-OH AD in serum from pregnant women and in placenta samples 43.
• A weak preparation (1%) of testosterone with 2 mg of estriol (1 g administered 2–3 times weekly) is often effective for improving vaginal dryness, dyspareunia and libido.

Estriol is a very weak estrogen and likewise cannot be converted to estradiol (65). There is little information regarding the safety of this https://vagatop.com/understanding-furosemide-uses-benefits-and-risks-2/ practice, particularly in women with prior breast cancer (66). Responses have been observed in premenopausal women with concomitant goserelin and AI treatment following tamoxifen failure (36,37). This concept is also being tested in the adjuvant setting with the Suppression of Ovarian Function (SOFT) and Tamoxifen or Exemestane Plus Ovarian Ablation (TEXT) trials. In the SOFT trial, women who are premenopausal after any adjuvant chemotherapy and have ER-positive tumours are randomised to tamoxifen, tamoxifen plus an LHRH analogue or exemestane plus the LHRH analogue (other types of ovarian ablation are also allowed). In the TEXT trial, premenopausal women who may or may not have received chemotherapy are randomised to receive tamoxifen or exemestane, both with an LHRH analogue.

The authors observed that AIs enabled more patients to achieve clinical benefits (CB) than TAM. The DoCB appeared slightly higher for AIs but did not significantly differ from TAM. In contrast, the PFS was statistically significantly different between the two groups in favor of AIs. Finally, even after excluding letrozole from the data, OS did not significantly differ between the two arms.