New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer

Abstract

Introduction: Endocrine therapy is the mainstay of treatment for a substantial proportion of hormone receptor positive (HR+) breast cancer (BC). Indeed, patients with metastatic disease not immediately life threatening may experience long disease control across several lines of endocrine therapy. The major limitation of this therapeutic approach is primary or acquired resistance. A better understanding of endocrine resistance has resulted in newer targeted agents to be added to endocrine therapy. Areas covered: This review highlights new findings in the treatment of HR+/HER2-BC, with a particular focus on new drugs from phase 3 development onwards.Expert opinion: Combining endocrine therapy with agents targeting putative mechanisms of endocrine resistance is a newer treatment paradigm in HR+ BC. Adding a biologically targeted agent to endocrine therapy results in improved response rate, and clinical benefit rate, and prolonged progression-free survival. A clear advantage in overall survival has not yet been reported. Combination therapy allows to delay chemotherapy but increases toxicities and costs, which are critical factors in decision making in the clinical practice. Moreover, identification and validation of biomarkers of response are needed. Ongoing and future trials should elucidate the role of these compounds in the treatment of HR +/HER2-BC. ARTICLE HISTORY

Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy

“…Given the complexity of these treatments, the identification of patient and tumor characteristics that can help inform when to use CDK4 & 6 inhibitors in the treatment paradigm and in which patients is a subject of considerable interest. 13,20,21 CDK4 & 6 inhibitor trials published to date have demonstrated treatment benefit for the addition of a CDK4 & 6 inhibitor to ET across all patient subgroups. 7-10,12,22 The present analyses of abemaciclib aim to determine independently prognostic subgroups, characterize the benefit of the addition of abemaciclib to endocrine therapy in these subgroups, and then determine those which derived the largest benefit from abemaciclib and those for which endocrine monotherapy may be an appropriate initial treatment.…”

New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death

“…Three hydroxamate-type pan-HDAC inhibitors have been approved by the US Food and Drug Administration (FDA) to date for the treatment of the following cancers: SAHA for the advanced forms of cutaneous T-cell lymphoma (CTCL) 5 , 6 , 32 ; Belinostat (Beleodaq) for refractory peripheral T-cell lymphoma (PTCL) 33 ; Panobinostat (Farydak) for the combinatorial treatment of multiple myeloma 34 . Furthermore, the cyclic depsipeptide FK228 (Romidepsin) was licensed by the US FDA for the treatment of CTCL 5 , 6 , 32 , and the 2-aminobenzamide-type HDAC inhibitor MS-275 (Entinostat), for breakthrough therapy in the treatment of advanced breast cancers 35 . On the other hand, HDAC inhibitors have emerged as an attractive therapeutic candidate for neurodegeneration in the last decade 36 , 37 because therapeutic options for neuroprotective therapies in subacute or chronic ischemic stroke currently remain very limited.…”

Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors

“…Since PI3K/AKT signaling pathway is one of the mechanisms underlying hormonal therapy resistance in advanced breast carcinoma, PI3K inhibitors were used in combination with fulvestrant or tamoxifen. Buparlisib, an inhibitor of a pan-isorform class I PI3K, taken orally, increased PFS in association with fulvestrant in postmenopausal women with advanced or metastatic estrogen receptor (ER) positive HER-2 negative breast cancer harboring PIK3CA mutations in a phase III clinical trial [ 121 , 122 ]. Buparlisib, is already being studied (phase IB) in association with lapatinib, a dual tyrosine kinase inhibitor which abrogates the HER-2/neu and EGFR pathways, in HER-2 positive advanced breast cancer that is resistant to trastuzumab, since the PI3K cascade is involved in trastuzumab resistance, and early conclusions demonstrate that this association is feasible for this kind of breast cancer [ 123 ].…”

“…When PIK3CA is mutated, the association of alpelisib, another alpha-specific PI3K inhibitor and fulvestrant showed good results in a phase I study of patients with advanced ER positive breast cancer on standard therapy [ 124 ]. There is a phase III study ongoing about the association of alpelisib or placebo with fulvestrant, and it aims to evaluate the PFS in two cohorts, one on mutated PIK3CA and the other with the wild type gene, and both stratified by the presence of lung and/or liver metastases, and prior CDK4/6 inhibitors treatment [ 122 ]. Other associations are being tested and in early phases of trials, as alpelisib and exemestane and letrozole, both antitumoral combinations, alpelisib and letrozole being tested for the safety and tolerability in patients with ER+ and HER-2 negative metastatic breast cancers that do not respond to endocrine therapy [ 122 ].…”

“…The data showed that taselisib was effective on metastatic or locally advanced solid malignancies that progressed or failed standard therapy, showing antitumor activity at low doses [ 125 ]. When associated with other inhibitors such as fulvestrant, taselisib has demonstrated a higher antitumoral response in HER-2 negative and ER positive breast cancers with PIK3CA mutations if compared with the wild type [ 122 ].…”