Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 2, pp 359–365 | Cite as

Impact of patient ethnicity on the metabolic and immunologic effects of PI3K–mTOR pathway inhibition in patients with solid tumor malignancies

  • Rahul Aggarwal
  • Jennifer Grabowsky
  • Noah Strait
  • Alyson Cockerill
  • Pamela Munster
Original Article

Abstract

Purpose

Inhibition of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is associated with metabolic and immunologic perturbations that impact drug tolerability. Here, we studied whether PI3 kinase/mTOR pathway inhibitors are associated with greater metabolic impact and decreased tolerability in Asian patients.

Methods

A retrospective analysis was conducted of consecutive patients with advanced malignancies treated on phase 1 trials of PI3K/mTOR inhibitors. Adverse events related to PI3K/mTOR inhibition, fasting plasma glucose (FPG), insulin, and c-peptide levels, hemoglobin A1c (HgbA1c), and T cell subsets were prospectively collected. Mann–Whitney and Chi-square tests were used to compare continuous and categorical variables, respectively, between Asian and Caucasian patients.

Results

A total of 103 patients (31 Asian; 72 Caucasian) were treated consecutively across five clinical trials. Baseline age, gender distribution, and metabolic parameters were comparable with the exception of lower median body mass index (BMI) in Asian patients (23.0 vs. 24.8 kg/m2, p = 0.024). There were no differences in drug tolerability, adherence, or duration of therapy. Asian patients experienced a higher incidence of grade ≥2 hyperglycemia (37.5 vs. 18.1 %, p = 0.03), and greater increases in FPG, HgbA1c, and insulin resistance. No differences in incidence or severity of mucositis, rash, or pneumonitis were observed. Drug effects on neutrophils, lymphocytes, and T cell subsets were similar.

Conclusions

PI3K/mTOR inhibitors have greater glycemic impact in Asian patients, despite similar baseline metabolic parameters, comparable dose intensity, and a lower median BMI. Further studies are warranted to explore the mechanisms underlying these differences and optimize dosing in Asian patients.

Keywords

Phosphatidylinositide 3-kinases (PI 3-kinases) PI3 kinase (PI3K) Mammalian target of rapamycin (mTOR) Ethnicity Glycemic indices Hyperglycemia Adverse effects 

Notes

Acknowledgments

The authors would like to acknowledge Anne Reinert and the nursing staff for the collection of data.

Conflict of interest

The authors do not have any financial support or conflicts of interest to disclose.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Rahul Aggarwal
    • 1
  • Jennifer Grabowsky
    • 1
  • Noah Strait
    • 1
  • Alyson Cockerill
    • 1
  • Pamela Munster
    • 1
  1. 1.Department of Medicine, Division of Hematology and OncologyUniversity of California San Francisco Helen Diller Family Comprehensive Cancer CenterSan FranciscoUSA

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