The NEOLETEXE trial: a neoadjuvant cross-over study exploring the lack of cross resistance between aromatase inhibitors

The aromatase inhibitor letrozole (Femar®/Femara®) and the aromatase inactivator exemestane (Aromasin®) differ in their biochemical effect on the aromatase enzyme. Letrozole is a competitive aromatase inhibitor while exemestane binds irreversibly to the aromatase enzyme. This pharmacological difference is of clinical interest since a lack of cross-resistance has been documented. It has been demonstrated in several clinical trials that exemestane may cause a disease regression following resistance to nonsteroidal aromatase inhibitors. The exact mechanism(s) behind this phenomenon is yet unknown. Here, we present the NEOLETEXE trial with the aim of exploring the individual mechanisms involved behind the observed lack of cross resistance. Clinical trial registration: The trial has been approved by the Regional Ethics Committee of South-East Norway (project number 2015/84).

Ligand- and Structure-Based Drug Design of Non-Steroidal Aromatase Inhibitors (NSAIs) in Breast Cancer

Aromatase is a multienzyme complex overexpressed in breast cancer and responsible for estrogen production. It is the potential target for designing anti-breast cancer drugs. Ligand and Structure-Based Drug Designing approaches (LBDD and SBDD) are involved in development of active and more specific Nonsteroidal Aromatase Inhibitors (NSAIs). Different LBDD and SBDD approaches are presented here to understand their utility in designing novel NSAIs. It is observed that molecules should possess a five or six membered heterocyclic nitrogen containing ring to coordinate with heme portion of aromatase for inhibition. Moreover, one or two hydrogen bond acceptor features, hydrophobicity, and steric factors may play crucial roles for anti-aromatase activity. Electrostatic, van der Waals, and p-p interactions are other important factors that determine binding affinity of inhibitors. HQSAR, LDA-QSAR, GQSAR, CoMFA, and CoMSIA approaches, pharmacophore mapping followed by virtual screening, docking, and dynamic simulation may be effective approaches for designing new potent anti-aromatase molecules.

A Case of Disease Improvement after Treatment with Everolimus plus Exemestane in a Patient with Hormone Receptor-Positive Metastatic Breast Cancer with Bone Metastases

Breast cancer is one of the most frequently diagnosed cancers and a leading cause of death in women worldwide. Despite significant advances in the treatment of hormone receptor-positive breast cancer, tumor metastasis occurs frequently and is associated with poor long-term prognosis. The mammalian target of rapamycin (mTOR) pathway plays a central role in cancer cell growth, proliferation, and resistance to endocrine therapies. Therefore, mTOR inhibitors such as everolimus in combination with nonsteroidal aromatase inhibitors might reverse endocrine resistance and improve clinical outcomes in patients. Here, we report on a case of infiltrating lobular carcinoma of the breast with metastases to the bone. Histopathologic analysis showed that the patient was estrogen and progesterone receptor positive and human epidermal growth factor-2 negative. This case represents the clinical spectrum of complications caused by metastasis: the patient experienced a considerable amount of skeletal-related complications, had previously received chemotherapy, and experienced disease progression while taking nonsteroidal aromatase inhibitors. After treatment with oral everolimus 10 mg daily plus oral exemestane 25 mg daily, the patient's disease was ameliorated. Combination therapy was well tolerated, with minimal adverse effects that were manageable with concomitant medications. Although further analyses in larger populations are necessary, the addition of everolimus to exemestane might provide an effective new treatment option for patients with bone metastasis.