PIK3CA Mutations as a Molecular Target for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

Abstract

Despite the significant achievements in the diagnosis and treatment of metastatic breast cancer (MBC), this condition remains substantially an incurable disease. In recent years, several clinical studies have aimed to identify novel molecular targets, therapeutic strategies, and predictive biomarkers to improve the outcome of women with MBC. Overall, ~40% of hormone receptor (HR)+/HER2− MBC cases harbor alterations affecting the (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. This pathway is a major target in oncogenesis, as it regulates growth, proliferation, cell survival, and angiogenesis. Lately, the pharmacologic targeting of PIK3CA in HR+/HER2− MBC has shown significant benefits after the occurrence of endocrine therapy resistance. The orally available α-selective PIK3CA inhibitor, alpelisib, has been approved in this setting. To perform an optimal patients' selection for this drug, it is crucial to adopt a tailored methodology. Clinically relevant PIK3CA alterations may be detected in several biospecimens (e.g. tissue samples and liquid biopsy) using different techniques (e.g. real-time PCR and next-generation sequencing). In this study, we provide an overview of the role of PIK3CA in breast cancer and of the characterization of its mutational status for appropriate clinical management.

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

“…Bone reabsorption causes the release of various growth factors that are stored in the bone matrix including insulin-growth factor 1 (IGF1), transforming growth factor β (TGF-β), fibroblast growth factor (FGFs) and platelet-derived growth factor (PDGF) [58][59][60]. Among these, IGF1 activates phosphoinositide 3-kinase (PI3K)/Akt mammalian target of rapamycin (mTOR) pathway, with subsequent breast cancer cell growth, proliferation, and migration into the bone [17,61,62]. Osteoblasts can also be regulated by metastatic tumor cell-derived factors including endothelin 1 (ET1), dickkopf 1 (DKK1), and the Wnt signaling cascade [36,[63][64][65][66].…”

“…However, their reliability and impact on patients' frailty remain a subject of debate [14]. This could be due to the lack of a complete understanding of the crosstalk between breast cancer circulating cells, tumor microenvironment, muscle tissue, and bone microenvironment [15][16][17][18][19]. Improved clinical management of patients with MBC to the bone not only requires an appropriate combination of systemic and bonetargeting agents, but also the precise identification of highly responsive patients using a precision medicine approach.…”

Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

“…However, the association of MLH1 with ATM activation and the formation of MSH2 complex with ATR/Chk1 activation are events that potentially play a role in these variable ET sensitivities [7,42]. Of note, a significant portion of HR+ breast cancers shows dysregulation of the phosphoinositide 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, which is also the main contributor to ET resistance [43,44]. Furthermore, actionable co-alterations in PIK3CA and DNA repair genes might lead to the activation of the human leukocyte antigen (HLA) molecules due to increased TMB and subsequent neoantigens production, particularly in the metastatic setting [13,45,46].…”

Akt Isoforms: A Family Affair in Breast Cancer

“…The lipid phosphatase activity of the tumor suppressor PTEN, which dephosphorylates PIP3, causes inactivation of PI3K, thereby inhibiting Akt [ 6 ]. Although mutations in Akt are rare, activating mutations in the catalytic subunit of p110 PI3K (PIK3CA) have been found in breast cancer [ 7 ]. In addition, amplification of HER2 as well as mutations in PTEN could also result in the activation of PI3K/Akt signaling.…”