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.

KEYWORDS:

• Abemaciclib
• alpelisib
• buparlisib
• CDK4/CDK6
• HDCA
• HR-positive breast cancer
• palbociclib
• PI3K
• ribociclib
• taselisib

Article highlights

• Endocrine resistance in HR+ BC is associated with different molecular mechanisms including deregulation of the ER pathway or acquired mutations in ESR1, constitutive activation of CDK4/6, cross talk with growth factor receptor signalling and epigenetic modifications by HDCA.

• Several targeted agents have been developed and have improved PFS in combination with standard endocrine agents thus leading to the FDA approval of two novel molecules, palbociclib and entinostat.

• PI3K inhibitors have demonstrated encouraging preliminary efficacy in HR+ MBC treatment, particularly in PIK3CA mutated tumours.

• Waiting results for OS impact on QoL must be taken into account when treating patients on endocrine therapy plus a biologic agent.

• All the ongoing trials are investigating prospectively on ‘mechanism of action based’ biomarkers of efficacy. These translational analyses will hopefully help us to identify the genetic alterations or pathways activation that are predictive of response in order to personalize treatments.

This box summarizes key points contained in the article.

Declaration of interest

F Montemurro is member of the speakers’ bureau for Hoffmann LaRoche and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

G Zucchini is supported by FPRC (ONLUS) fondi 5 mille 2012 Ministero della Salute.