Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors

Abstract

In this review, we discuss biomarkers of response and resistance to PI3K inhibitors (PI3Ki) in estrogen receptor-positive breast cancer, both in the early and advanced settings. We analyse data regarding PIK3CA mutations, PI3K pathway activation, PTEN expression loss, Akt signalling, insulin levels, 18FFDG-PET/CT imaging, FGFR1/2 amplification, KRAS and TP53 mutations. Most of the discussed data comprise retrospective and exploratory studies, hence many results are not conclusive. Therefore, among all of these biomarkers, only PIK3CA mutations have proved to have a predictive value for treatment with the α-selective PI3Ki alpelisib (SOLAR-1 trial) and the β-sparing PI3Ki taselisib (SANDPIPER trial) in the advanced setting. Since the accuracy of current individual biomarkers is not optimal, a composite biomarker, including DNA, RNA and protein expression data, to more precisely assess the PI3K/AKT/mTOR pathway activation status, may arise as a promising approach. Finally, we describe the rational for new combination therapies involving PI3Ki and anti-HER2 agents, chemotherapy, CDK4/6 inhibitors, mTOR inhibitors or new endocrine treatments and discuss the ongoing trials in this field.

Keywords: PI3K inhibitors; PIK3CA; breast neoplasms; gene sequencing; predictive biomarkers.

Figure 1.

Mechanisms of resistance to PI3K inhibitors in estrogen receptor (ER)-positive breast cancer and current and future drug combination strategies involving PI3K inhibitors. In PIK3CA-mutated breast tumours, resistance to PI3K inhibitors can be mediated by multiple mechanisms, including activation of alternative pathways that drive cell proliferation (e.g. RAS/MEK/ERK pathway, ER pathway, or HER2 pathway); by signalling via other PI3K isoforms when a specific subunit is blocked; by activation of downstream effectors in the PI3K pathway such as AKT and mTOR; by loss of regulators of PI3K signalling such as PTEN; or by epigenomic crosstalk between PI3K and ER pathways, resulting in upregulation of ER-dependent transcription. Ab, monoclonal antibody; AR, androgen receptor; CDK4/6i, CDK4/6 inhibitors; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; IGFR1, insulin growth factor receptor 1; mTOR, mTOR inhibitors; PI3Ki, PI3K inhibitors; SERD, selective estrogen receptor degraders; T-DM1, ado-trastuzumab emtansine; TKI, tyrosine kinase inhibitor. Dashed arrows, inhibitory function; bold arrows, activation function. Note: within each drug class, we have only included compounds that have been or that are currently being tested in combination with PI3K inhibitors in clinical trials (see Tables 2 and 3 for more details).