Moving beyond endocrine therapy for luminal metastatic breast cancer in the precision medicine era: looking for new targets

ABSTRACT

Introduction: Hormone receptor-positive (HR+) breast cancer (BC) is the most frequent BC subtype, for which estrogen receptor (ER)-signaling blockade still represents the cornerstone of treatments. Nevertheless, almost all HR+ BC patients develop resistance to endocrine therapy, a critical therapeutic unmet need for BC patients. Recent advances in genomic medicine allowed for a more detailed identification and better characterization of the mechanisms underlining endocrine resistance and led to the development of targeted agents potentially able to restore endocrine sensitivity, thus improving disease control and potentially survival.

Areas covered: New drugs in the early phase of development for HR-positive metastatic BC (MBC) treatment are here outlined. PI3K/AKT/mTOR, FGFR, and IGFRs are the main pathways addressed, and evidences about HER2 blockade in triple-positive diseases are also reported. New hormonal agents active against estrogen receptor 1 (ESR1)-mutant MBC are presented. A brief mention of biological agents not targeting intracellular signaling hubs, such as histone-deacetylase inhibitors and immunotherapy drugs, is finally provided.

Expert opinion: promising results have been reported for the majority of new drugs under development. Despite this, a ‘precision medicine approach’ still has to demonstrate a benefit in this disease. Identification of reliable predictive biomarkers should be a key objective of future researches.

KEYWORDS:

• Breast cancer
• endocrine resistance
• endocrine therapy
• precision medicine
• new drugs

Article Highlights

• Combination of CDK 4/6 inhibitors and endocrine therapy (ET) represents the standard of care in first-line setting of HR-positive metastatic BC (MBC), but the optimal therapeutic choice after progressing on this regimen is still debated.

• Up-regulation of different oncogenic pathways is a well-known mechanism of resistance to ET, with PI3K/AKT/mTOR, FGFR, and IGFR as the most common altered signaling pathways. Several targeted agents that inhibit these pathways are currently under development in this setting, along with HER2 blockade in triple-positive diseases.

• New endocrine agents with a higher efficacy on ESR1-mutated MBC are also currently under investigation in several clinical trials,

• Implementation of immunotherapy for MBC is still investigational, with low response rates recorded in early phase trials. In this setting, the implementation of proper biomarkers might allow an adequate patients’ selection across several fields of immune-oncology.

• Distinguishing between subclonal and truly actionable ‘trunk’-driver alterations as well as the identification of reliable predictive biomarkers represent the main challenges of precision medicine in the context of MBC.

Acknowledgments

We thank Dario Trapani for supporting proofreading.

Declaration of interest

Giuseppe Curigliano has received honoraria from Pfizer, Novartis, Lilly, Roche; fees for expert testimony and medical education from Pfizer; and has participated in advisory boards for Pfizer, Roche, Lilly, Novartis, Seattle Genetics, Celltrion. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.