The Future of ER+/HER2− Metastatic Breast Cancer Therapy: Beyond PI3K Inhibitors

Abstract

Most breast cancers express the estrogen receptor (ER) receptor and are negative for the human epidermal growth factor receptor 2 (HER2) receptor. ER+/HER2-cancers are treated with hormone-based therapies in the adjuvant setting and derive significant survival benefit from these therapies in the metastatic setting. However, hormone resistance develops in most metastatic patients. An increased understanding of the biology of ER+/HER2-breast cancers has led to the development of new therapies for this disease including CDK4/6 inhibitors and PI3K inhibitors. Several other neoplastic processes are targeted by novel drugs in clinical development, addressing cancer vulnerabilities. These include newer ways to block the ER and targeting the HER2 receptors in ER+/HER2cancers expressing HER2 in low levels not qualifying for clinical positivity. In addition, promising therapeutic options include targeting other surface receptors or their downstream pathways, as well as targeting the apoptotic machinery and boosting the immune response which is initially insufficient in these cancers. A selection of new drugs in advanced development for ER+/HER2-breast cancer will be discussed in this review.Estrogen receptor positive (ER)+/human epidermal growth factor receptor 2 negative HER2-breast cancers constitute the most common subset of breast cancer representing about three fourths of these cancers. The backbone of their systemic therapy consists of hormonal therapies that block the function of ER through various mechanisms (1). These include blockade of the receptor itself in breast cancer cells, blockade of the production of its major ligand, estradiol, or degradation of the receptor. However, a subset of ER+/HER2-breast cancers, mostly corresponding to the genomic luminal B genotype, are resistant to hormonal manipulations from the outset of therapies. More commonly, resistance eventually develops with protracted use of hormone receptor targeting therapies. Resistance to endocrine therapies, either primary or secondary, represents a major block in the success of ER+/HER2-breast cancer therapeutics and it is thus intensely investigated. Various mechanisms imparting resistance have been identified and elucidated in preclinical models and several have been confirmed in the clinic. Successful development of drugs that prevent or circumvent hormone resistance has been accomplished with the introduction of mTOR inhibitors, CDK4/6 inhibitors and more recently, PI3K inhibitors, for PIK3CA mutated cancers (2, 3). However, these targeted drugs address only specific pathways of resistance and are effective either only in groups of patients with specific molecular defects or for only a defined time period before tumors develop secondary resistance. Median progression free survival (PFS), for example, in the combination arm of the phase III trial of letrozole with the CDK4/6 inhibitor palbociclib in the first line setting was 24.8 months (4). Similarly, median PFS was 25.3 months with the combination of letrozole with ribociclib and 23.8 mo...

Biomarkers of everolimus efficacy in breast cancer therapy

“…73 Besides mTOR inhibitors, several other drugs inhibiting the PI3 K/ AKT/ mTOR pathway have entered the clinic or are in development, including PI3 K inhibitors, AKT inhibitors and dual PI3 K/ mTOR inhibitors. 7,74 However, despite inhibiting proteins in the same pathway, each class of drugs have unique effects stemming from acting at different levels of the pathway. As a result, they produce variable feedback and feed-forward loop regulations, that also depend on concomitant molecular alterations in related pathways.…”

“…[3][4][5][6] Several other targeted therapies are in development. 7 The mTOR kinase inhibitor everolimus is another targeted therapy that is indicated in metastatic ER positive, HER2 negative breast cancers in combination with hormonal therapy (Figure 1). It was the first targeted therapy to be introduced in this most common sub-type of breast cancer, after progression on hormonal therapy alone.…”

AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclibversusletrozole plus palbociclib for previously untreated ER+/HER2– advanced breast cancer

“…2 The majority of breast cancers are hormone receptor positive (HR+), including both estrogen receptor–positive (ER+) cancers that account for approximately 75% of all breast cancers and progesterone receptor–positive cancers; the most common subtype is ER+/human epidermal growth factor receptor 2 negative (HER2–). 3 , 4 …”

High Mutation Burden in ER-Positive/HER2-Negative/Luminal Breast Cancers

“…Targeted therapies that have improved outcomes in breast cancers and are currently in the clinical armamentarium include CDK kinase inhibitors and PI3K kinase inhibitors in metastatic ER-positive breast cancers, PARP inhibitors for cancers with BRCA1 or BRCA2 mutations, and immune checkpoint inhibitors for triple-negative cancers and cancers with microsatellite instability [ 3 , 4 , 5 , 6 ]. Other targeted therapies are in various stages of development, and some of them will undoubtfully find their way to the clinic [ 7 , 8 ].…”