Lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients: the potential role of the adipokine leptin

Purpose The aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known “lack of cross-resistance”. Methods Postmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using Luminex xMAP technology (multiple ELISA). Results Serum levels of leptin were significantly decreased during treatment with exemestane (p < 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo. Conclusions Our findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with the non-steroidal aromatase inhibitor letrozole. Our findings provide new insights into the influence of clinically important aromatase inhibitors on cytokine levels in vivo that contribute to the understanding of the clinically observed lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients. Trial registration Registered on March 23rd 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).

Relevance of Aromatase Inhibitors in Breast Cancer Treatment

: Efficacious treatment for breast cancer is still a challenge despite the presence of various treatment options. Aromatase enzyme present in the breast tissue is responsible for estrogen formation from androgens. Aromatase inhibitors manifest remarkably ameliorated therapeutic efficacy as compared to the current therapeutic options available and exhibit a better safety profile as compared to the other drugs. Clinical resistance to aromatase inhibitors is perceived as a lack of growth inhibition by aromatase inhibitors treatment and cancer therapy becomes ineffective in causing a decrease in the size of the tumor. Naturally extracted aromatase inhibitors have a huge positive impact on vitality and living standards. This review article highlights the particulars about the currently approved steroidal and non-steroidal aromatase inhibitors for clinical use, adverse effects associated with their use and approach to tackling the problem, various strategies to overcome aromatase inhibitors resistance, information on the synthesis of various peculiar aromatase inhibitors which can prove as highly efficient and potent drugs in the near future and the drugs of natural and semi-synthetic origin which can demonstrate to be more efficient, potent and less-toxic than conventional therapy.

Bone safety profile of steroidal aromatase inhibitor in comparison to non-steroidal aromatase inhibitors in postmenopausal women with breast cancer: A network meta-analysis.

527 Background: Steroidal and non-steroidal aromatase inhibitors (AIs) provide better therapeutic response in comparison to other endocrine therapies in the adjuvant treatment of breast cancer (BC). They interfere with bone turnover which may lead to increased incidence of bone related safety events. There are no head-on studies comparing the incidence of bone safety events and hence we performed this network meta-analysis (NMA) to compare the incidence of bone safety events among patients treated with steroidal and non-steroidal AIs. Methods: Literature searches were performed in PubMed and Embase with key words to identify randomized controlled trials in BC patients treated with AIs in adjuvant settings compared against tamoxifen or other AIs, reporting any bone-related safety events. The study was designed as per PRISMA guidelines; publication bias was evaluated by comparison-adjusted funnel plots. Bayesian NMA was done by R software (ver 3.2), GemtC package. Odds ratio (OR) and the surface under the cumulative ranking curve (SUCRA) values were used to interpret the results. Results: 15 studies reporting 6 different bone-related endpoints were included. Treatment with steroidal AI, exemestane led to lower incidence of bone pain (OR Vs anastrozole and letrozole: 0.59, p=0.63; 0.54, p=0.75), fracture episodes (OR Vs anastrozole and letrozole: 0.84, p=0.41; 0.85, p=0.73), joint stiffness (OR Vs anastrozole: 0.55, p=0.73) and osteoporosis (OR Vs anastrozole and letrozole: 0.86, p=0.41; 0.74, p=0.29) (Table) in comparison to letrozole and anastrozole. Reduction in bone mineral density was also lesser in exemestane than anastrozole (mean reduction in hip: 1.08; lumbar spine: 1.34). SUCRA values suggested exemestane to be the drug with maximum likelihood for reducing the incidence of bone-related adverse events. Conclusions: This NMA suggested that bone-related safety events might be lower in early BC patients treated with exemestane in comparison to non-steroidal AIs, anastrozole and letrozole. Although there was no statistical significance, further head-on studies are required to substantiate our results.[Table: see text]

Mechanisms of allosteric and mixed mode aromatase inhibitors

Aromatase (Cyp19) catalyzes the last biosynthetic step of estrogens in mammals and is a primary drug target for hormone-related breast cancer. However, treatment with aromatase inhibitors is often associated with adverse effects and drug resistance. In this study, we used virtual screening targeting a predicted cytochrome P450 reductase binding site on aromatase to discover four novel non-steroidal aromatase inhibitors. The inhibitors have potencies comparable to the noncompetitive tamoxifen metabolite, endoxifen. Our two most potent inhibitors, AR11 and AR13, exhibit both mixed-type and competitive-type inhibition. The cytochrome P450 reductase-Cyp19 coupling interface likely acts as a transient binding site. Our modeling shows that our inhibitors bind better at different sites near the catalytic site. Our results predict the location of multiple ligand binding sites on aromatase. The combination of modeling and experimental results supports the important role of the reductase binding interface as a low affinity, promiscuous ligand binding site. Our new inhibitors may be useful as alternative chemical scaffolds that may show different adverse effects profiles than current clinically used aromatase inhibitors.

Lack of Cross-resistance Between Non-steroidal and Steroidal Aromatase Inhibitors in Breast Cancer Patients: The Potential Role of the Adipokine Leptin.

Background: The aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known “lack of cross-resistance”. Experimental design: Postmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using the Luminex xMAP technology (multiple ELISA). Results: Serum levels of leptin were significantly decreased during treatment with exemestane (p < 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo. Conclusions: Our findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with non-steroidal aromatase inhibitors. Our findings provide a reasonable explanation for the clinically observed lack of cross-resistance between nonsteroidal and steroidal aromatase inhibitors in breast cancer patients.Trial registration: registered on March 23rd. 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).

Development of Steroidal Aromatase Inhibitors as Potential Anti-breast Cancer Agents

Breast cancer is the most prevalent type of cancer and one of the leading causes of death among all the cancers affecting women worldwide. Preliminary cause of development of tumors in the breast cancer in post-menopausal women is mostly the increased estrogen levels in the body which could be the result of overexpression of aromatase CYP450 i.e. CYP19A1. Aromatase is the only enzyme present in humans that brings about aromatization of A-ring of 19-carbon androgens to form 18-carbon estrogens. Inhibiting aromatase enzyme thereby decreasing the estrogen levels in the postmenopausal women has been considered as an important strategy for the management of breast cancer. Three generations of aromatase inhibitors including steroidal viz. testolactone, formestane, exemestane and non-steroidal viz. aminoglutethimide, fadrozole, letrozole, anastrozole, the two classes of drugs have been approved for clinical use for the treatment of breast cancer. A large number of research and review articles have been reported so far describing the therapeutic efficacy of steroidal and non-steroidal aromatase inhibitors. However, steroidal aromatase inhibitors, being more selective inhibitors and having certain other advantages, overruled the discovery of novel aromatase inhibitors compared to the non-steroidal aromatase inhibitors which lack selectivity for CYP450 aromatase. In this review, efforts have been made to describe the developments of steroidal aromatase inhibitors to date.