Dataset Information

Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data.

ABSTRACT: Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2 negative) breast cancer accounts for over 70% of all breast cancers. There has been much advancement in the treatment of HR+/HER2 negative metastatic breast cancer (MBC), in particular the development of more tailored and targeted therapies. Recently, greater understanding of the role of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway in breast cancer has led to the development of PI3K inhibitors, which have proven to be effective in the treatment of HR+/HER2 negative MBC. In this review, we will discuss the role of the PI3K/AKT/mTOR pathway in breast cancer and therapies that have been developed to inhibit PI3K. We will discuss in detail the development of PI3K inhibitor alpelisib, indications for use in HR+/HER2 negative MBC, safety and tolerability and the future direction of this therapy in the treatment of breast cancer.

SUBMITTER: Armaghani AJ

PROVIDER: S-EPMC7680678 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data.

Armaghani Avan J AJ Han Hyo Sook HS

Breast cancer (Dove Medical Press) 20201118

Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2 negative) breast cancer accounts for over 70% of all breast cancers. There has been much advancement in the treatment of HR+/HER2 negative metastatic breast cancer (MBC), in particular the development of more tailored and targeted therapies. Recently, greater understanding of the role of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway in breast cancer has led to the develo ...[more]

PMID: 33239910

Similar Datasets

Project description:The PI3K/AKT/mTOR pathway has long been known to play a major role in the growth and survival of cancer cells. Breast tumors often harbor PIK3CA gene alterations, which therefore constitute a rational drug target. However, it has taken many years to demonstrate clinically-relevant efficacy of PI3K inhibition and eventually attain regulatory approvals. As data on PI3K inhibitors continue to mature, this review updates and summarizes the current state of the science, including the prognostic role of PIK3CA alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3K? inhibitor, alpelisib; PIK3CA mutation detection techniques; and adverse effect management. PIK3CA-mutated breast carcinomas predict survival benefit from PI3K inhibitor therapy. The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. Alpelisib is better tolerated, with a more manageable toxicity profile; the principal adverse events, hyperglycemia, rash and diarrhea, can be mitigated by intensive monitoring and timely intervention, thereby enabling patients to remain adherent to clinically beneficial treatment. Alpelisib plus endocrine therapy shows promising efficacy for treating postmenopausal women with HR+/HER2- advanced breast cancer. Available evidence supporting using alpelisib after disease progression on first-line endocrine therapy with or without CDK4/6 inhibitors justifies PIK3CA mutation testing upon diagnosing HR+/HER2- advanced breast cancer, which can be done using either tumor tissue or circulating tumor DNA. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.

Project description:Fulvestrant is the first selective estrogen receptor (ER) downregulator available in clinical practice. It is a pure antiestrogen with no agonistic effects, leading to degradation of ER alpha, with activity in tamoxifen-resistant breast cancer (BC) models. Pharmacokinetic and pharmacodynamic studies and several postmarketing clinical trials led to the definition of the optimal dose at 500 mg intramuscularly on days 1, 15, and 29 and then every 28 days. Targeting ER alpha, fulvestrant is a cornerstone of treatment in luminal BCs, whose growth is largely driven by the ER pathway. In endocrine therapy-naïve patients with hormone receptor-positive, HER2- advanced BC (ABC), fulvestrant yielded significantly longer progression-free survival compared to anastrozole in the Phase III FALCON study. Due to its mechanism of action and pharmacokinetic properties, fulvestrant is an ideal backbone for combination therapies. Preclinical studies have shown synergism with drugs acting on signaling pathways involved in the development of endocrine resistance, among which the cyclin D/cyclin-dependent kinase 4-6/retinoblastoma pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, contributing to overcoming or delaying endocrine resistance. In the Phase III PALOMA-3 trial, a combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib with fulvestrant significantly improved progression-free survival over fulvestrant alone in women with hormone receptor positive, HER2- ABC progressing during prior endocrine therapy. This led to approval of the combination in this clinical setting. Similar results were obtained with abemaciclib and ribociclib. Combination with pan-PI3K inhibitors, though showing some efficacy, was hampered by the toxicity of these agents, and studies in combinations with more selective inhibitors of the α-catalytic subunit of PI3K are ongoing. Fulvestrant has shown partial activity also in patients with tumors harboring mutations of the ESR1 gene. It is thus a key drug in the treatment of ABC, whose role in combination with new targeted agents is still evolving.

Dataset Information

Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data.

Publications

Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure