Abstract
Dysregulation of phosphoinositide 3-kinase (PI3K) signaling is highly implicated in tumorigenesis, disease progression, and the development of resistance to the current standard of care treatments in breast cancer patients. This review discusses the role of PI3K pathway in breast cancer and evaluates the clinical development of PI3K inhibitors in both early and metastatic breast cancer settings. Further, this review examines the evidence for the potential synergistic benefit for the combination treatment of PI3K inhibition and immunotherapy in breast cancer treatment.
Highlights
Breast cancer is the most frequent cancer type in women worldwide (Bray et al, 2018)
After resistance develops to hormone therapy, chemotherapy becomes the only standard treatment option (Cardoso et al, 2009); 15–20% of patients are diagnosed as HER2+ (Howlader et al, 2014)
With the approval of the alpha selective phosphoinositide 3-kinase (PI3K) inhibitor alpelisib in HR+/HER2− PIK3CA-mutated advanced/metastatic breast cancer patients after progression on endocrine therapy (ET), several clinical trials evaluate its efficacy in advanced triple-negative breast cancer (TNBC), and HER2+ subtypes are ongoing (NCT04208178; NCT04216472)
Summary
Breast cancer is the most frequent cancer type in women worldwide (Bray et al, 2018). Further research that elucidates the possible mechanism of PI3K inhibition, intrinsic and acquired resistance, is essential to enhance the durability of clinical benefit with targeted combination treatment tailored to specific subtypes of breast cancer and the mutational status of the patients. Severe diarrhea associated with PI3Kδ isoform inhibition is due to the impairment of colon macrophage functionality and pro-inflammatory response (Uno et al, 2010) This again justifies selective targeting of PI3K isoforms based on the observed mutational status of the patients to reduce AEs. Overall, despite the importance of the PI3K pathway in breast cancer and therapy resistance, many PI3K inhibitors used as monotherapy reported limited efficacy and high toxicity profile in current clinical trials across breast cancer subtypes. This necessitates the examination of PI3K inhibition in combination with other types of therapies to potentially maximize antitumor effects
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