Phosphoinositide 3-kinase inhibitors in advanced breast cancer: A systematic review and meta-analysis

Jacques Raphael; Danielle Desautels; Kathleen I Pritchard; Ekaterina Petkova; Prakeshkumar S Shah

doi:10.1016/j.ejca.2017.12.010

Phosphoinositide 3-kinase inhibitors in advanced breast cancer: A systematic review and meta-analysis

Eur J Cancer. 2018 Mar:91:38-46. doi: 10.1016/j.ejca.2017.12.010. Epub 2018 Jan 11.

Authors

Jacques Raphael¹, Danielle Desautels², Kathleen I Pritchard³, Ekaterina Petkova⁴, Prakeshkumar S Shah⁵

Affiliations

¹ Institute of Health Policy, Management and Evaluation, University of Toronto, Canada; Department of Oncology, Western University, London Regional Cancer Program, London, ON, Canada. Electronic address: raphaeljack13@hotmail.com.
² Institute of Health Policy, Management and Evaluation, University of Toronto, Canada; Department of Medical Oncology and Haematology, University of Manitoba and CancerCare Manitoba, MB, Canada.
³ Institute of Health Policy, Management and Evaluation, University of Toronto, Canada; Division of Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, ON, Canada.
⁴ Department of Medicine, Sunnybrook Health Sciences Centre, ON, Canada.
⁵ Institute of Health Policy, Management and Evaluation, University of Toronto, Canada; Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

PMID: 29331750
DOI: 10.1016/j.ejca.2017.12.010

Abstract

Phosphoinositide 3-kinase (PI3K) inhibitors may overcome drug resistance and improve advanced breast cancer (ABC) outcomes. We conducted a systematic review and meta-analysis to assess the efficacy and safety of adding a PI3K inhibitor to the standard of care (SOC) treatment in ABC. The electronic databases Ovid, PubMed, Cochrane Central Register of Controlled Trials and Embase, were searched for relevant randomised trials. Pooled hazard ratios (HRs) for progression-free survival (PFS) and pooled risk ratios (RRs) for objective response rates (ORRs), disease control rates (DCRs) and toxicity were meta-analysed using the Mantel-Haenszel method and generic inverse variance. Five studies were included. In unselected patients, the addition of a PI3K inhibitor decreased the risk of progression by 21% (2329 participants, HR = 0.79; 95% confidence interval [CI], 0.71-0.88). A marginal improvement in ORR (2329 participants, RR = 1.26; 95% CI, 1.01-1.57) and no improvement in DCR (2146 participants, RR = 1.05; 95% CI, 0.94-1.18) were achieved with a significant increase in toxicity of any grade (2386 participants, RR = 1.05; 95% CI, 1.03-1.06) and of grade III and higher (2386 participants, RR = 1.91; 95% CI, 1.76-2.08). A PFS benefit was seen in patients with and without PI3K pathway activation assessed on tumour and only in patients with an activated PI3K pathway when it was assessed from the plasma using circulating tumour DNA (ct-DNA) analysis. The addition of a PI3K inhibitor decreases the risk of progression in unselected ABC patients and particularly in patients with an activated PI3K pathway detected on ct-DNA analysis. However, their significant dose-limiting toxicity is a limiting factor. Selective PI3K inhibitors are being tested to assess whether these better-tolerated agents have a role in ABC treatment.

Keywords: Advanced breast cancer; Meta-analysis; PI3K inhibitor; Progression-free survival; Systematic review; Toxicity.

Publication types

Meta-Analysis
Review
Systematic Review

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / mortality
Breast Neoplasms / pathology
Chi-Square Distribution
Clinical Trials, Phase II as Topic
Clinical Trials, Phase III as Topic
Disease Progression
Disease-Free Survival
Female
Humans
Odds Ratio
Phosphatidylinositol 3-Kinase / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / adverse effects
Protein Kinase Inhibitors / therapeutic use*
Randomized Controlled Trials as Topic
Risk Factors
Signal Transduction / drug effects
Time Factors
Treatment Outcome

Substances

Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Phosphatidylinositol 3-Kinase