Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial
“…At present, activated PI3K pathway biomarkers in HR+, HER2− ABC do not guide treatment decisions as no CDK4/6 or mTOR inhibitors currently approved for HR+, HER2− ABC have demonstrated superior efficacy in patients with versus without PIK3CA‐ mutated tumors . However, phase III trials of investigational PI3K inhibitors suggest patients may derive differential benefit depending on their tumors’ PIK3CA mutation status . At present, activated PI3K pathway biomarkers in HR+, HER2− ABC do not guide treatment decisions as no CDK4/6 or mTOR inhibitors currently approved for HR+, HER2− ABC have demonstrated superior efficacy in patients with versus without PIK3CA‐ mutated tumors.…”
Resistance to endocrine therapy (ET) is common in patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Consequently, new targeted treatment options are needed in the post‐ET setting, with validated biomarkers to inform treatment decisions. Hyperactivation of the phosphoinositide 3‐kinase (PI3K) signaling pathway is common in ABC and is implicated in resistance to ET. The most frequent mechanism of PI3K pathway activation is activating mutations or amplification of PIK3CA, which encodes the α‐isoform of the catalytic subunit of PI3K. Combining buparlisib, a pan‐PI3K‐targeted agent, with ET demonstrated modest clinical benefits in patients with aromatase inhibitor‐resistant, HR+, human epidermal growth receptor 2 negative (HER2−) ABC in two phase III trials. Importantly, greater efficacy gains were observed in individuals with PIK3CA‐mutated disease versus PIK3CA‐wild‐type tumors. Although the challenging safety profile did not support widespread use of this treatment combination, isoform‐selective PI3K inhibitors may improve tolerability. In early clinical trials, promising disease control benefits were demonstrated with the PI3K isoform‐selective inhibitors alpelisib and taselisib in patients with PIK3CA‐mutated HR+, HER2− ABC. Ongoing biomarker‐guided phase II/III studies may provide further opportunities to identify patients most likely to benefit from treatment with PI3K inhibitors and provide insight into optimizing the therapeutic index of PI3K inhibitors. Challenges facing the implementation of routine PIK3CA mutation testing must be addressed promptly so robust and reproducible genotyping can be obtained with liquid and tumor biopsies in a timely and cost‐effective manner.
Implications for Practice
The development of phosphoinositide 3‐kinase (PI3K) inhibitors, especially those that selectively target isoforms, may be an effective strategy for overcoming endocrine therapy resistance in hormone receptor positive, human epidermal growth receptor 2 negative advanced breast cancer. Early‐phase studies have confirmed that patients with PIK3CA mutations respond best to PI3Kα‐isoform inhibition. Ongoing phase III trials will provide further data regarding the efficacy and safety of PI3K inhibitors in patients with different biomarker profiles.
“…At present, activated PI3K pathway biomarkers in HR+, HER2− ABC do not guide treatment decisions as no CDK4/6 or mTOR inhibitors currently approved for HR+, HER2− ABC have demonstrated superior efficacy in patients with versus without PIK3CA‐ mutated tumors . However, phase III trials of investigational PI3K inhibitors suggest patients may derive differential benefit depending on their tumors’ PIK3CA mutation status . At present, activated PI3K pathway biomarkers in HR+, HER2− ABC do not guide treatment decisions as no CDK4/6 or mTOR inhibitors currently approved for HR+, HER2− ABC have demonstrated superior efficacy in patients with versus without PIK3CA‐ mutated tumors.…”
Resistance to endocrine therapy (ET) is common in patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Consequently, new targeted treatment options are needed in the post‐ET setting, with validated biomarkers to inform treatment decisions. Hyperactivation of the phosphoinositide 3‐kinase (PI3K) signaling pathway is common in ABC and is implicated in resistance to ET. The most frequent mechanism of PI3K pathway activation is activating mutations or amplification of PIK3CA, which encodes the α‐isoform of the catalytic subunit of PI3K. Combining buparlisib, a pan‐PI3K‐targeted agent, with ET demonstrated modest clinical benefits in patients with aromatase inhibitor‐resistant, HR+, human epidermal growth receptor 2 negative (HER2−) ABC in two phase III trials. Importantly, greater efficacy gains were observed in individuals with PIK3CA‐mutated disease versus PIK3CA‐wild‐type tumors. Although the challenging safety profile did not support widespread use of this treatment combination, isoform‐selective PI3K inhibitors may improve tolerability. In early clinical trials, promising disease control benefits were demonstrated with the PI3K isoform‐selective inhibitors alpelisib and taselisib in patients with PIK3CA‐mutated HR+, HER2− ABC. Ongoing biomarker‐guided phase II/III studies may provide further opportunities to identify patients most likely to benefit from treatment with PI3K inhibitors and provide insight into optimizing the therapeutic index of PI3K inhibitors. Challenges facing the implementation of routine PIK3CA mutation testing must be addressed promptly so robust and reproducible genotyping can be obtained with liquid and tumor biopsies in a timely and cost‐effective manner.
Implications for Practice
The development of phosphoinositide 3‐kinase (PI3K) inhibitors, especially those that selectively target isoforms, may be an effective strategy for overcoming endocrine therapy resistance in hormone receptor positive, human epidermal growth receptor 2 negative advanced breast cancer. Early‐phase studies have confirmed that patients with PIK3CA mutations respond best to PI3Kα‐isoform inhibition. Ongoing phase III trials will provide further data regarding the efficacy and safety of PI3K inhibitors in patients with different biomarker profiles.
“…The approval was based on a randomized double-blind multicenter trial (BOLERO-2), where the combination significantly improved disease free survival (DFS) compared to exemestane alone (7.8 months versus 3.2 months) [36]. Recently, the results from a phase 3 trial involving buparlisib, a pan-PI3K inhibitor targeting all four isoforms of class I PI3K (α, β, δ, and γ), were presented and published [37]. Although the efficacy data of buparlisib supports the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations, the safety profile of buparlisib plus fulvestrant did not support its further development in that setting.…”
Several mechanisms of resistance have been identified, underscoring the complex nature of estrogen receptor (ER) signaling and the many connections between this pathway and other essential signaling pathways in breast cancer cells. Many therapeutic targets of cell signaling and cell cycle pathways have met success with endocrine therapy and remain an ongoing area of investigation. This review focuses on two major pathways that have recently emerged as important opportunities for therapeutic intervention in endocrine resistant breast tumors: PI3K/AKT/mTOR cell signaling and cyclinD1/cyclin-dependent kinase 4/6 cell cycle pathways. Additionally, we highlight individual and combination strategies in current clinical trials that target these pathways and others under investigation for the treatment of ER positive breast cancer.
“…To date, no information from randomized sequencing trials is available but some data suggest limited activity of endocrine therapy alone in patients pretreated with a combination of endocrine therapy and targeted drugs [2, 3]. Therefore, I would suggest that a combination of endocrine therapy and everolimus may be reasonable with PIK3CA inhibitors being a potential future option.…”
Section: Question 3: What Is Your Preferred Treatment After Progressimentioning
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