Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

Virginia G. Kaklamani, Andrea L. Richardson, Carlos L Arteaga

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalOncologist
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

1-Phosphatidylinositol 4-Kinase
Biomarkers
Hormones
Breast Neoplasms
Growth
Protein Isoforms
Therapeutics
Mutation
Safety
Aromatase Inhibitors
Catalytic Domain
Neoplasms
Clinical Trials
Biopsy

Keywords

  • Alpelisib
  • Breast neoplasms
  • Buparlisib
  • Molecular targeted therapy
  • PIK3CA protein, human
  • Taselisib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{06134cf443834db8b67863bcc931bcc4,
title = "Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer",
abstract = "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.",
keywords = "Alpelisib, Breast neoplasms, Buparlisib, Molecular targeted therapy, PIK3CA protein, human, Taselisib",
author = "Kaklamani, {Virginia G.} and Richardson, {Andrea L.} and Arteaga, {Carlos L}",
year = "2019",
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doi = "10.1634/theoncologist.2018-0314",
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journal = "Oncologist",
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T1 - Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

AU - Kaklamani, Virginia G.

AU - Richardson, Andrea L.

AU - Arteaga, Carlos L

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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