PMID- 24934865
OWN - NLM
STAT- MEDLINE
DCOM- 20141028
LR  - 20221207
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 74
IP  - 2
DP  - 2014 Aug
TI  - Impact of patient ethnicity on the metabolic and immunologic effects of PI3K-mTOR 
      pathway inhibition in patients with solid tumor malignancies.
PG  - 359-65
LID - 10.1007/s00280-014-2510-0 [doi]
AB  - 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/m(2), 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.
FAU - Aggarwal, Rahul
AU  - Aggarwal R
AD  - Department of Medicine, Division of Hematology and Oncology, University of 
      California San Francisco Helen Diller Family Comprehensive Cancer Center, 1600 
      Divisadero Street, San Francisco, CA, 94143, USA.
FAU - Grabowsky, Jennifer
AU  - Grabowsky J
FAU - Strait, Noah
AU  - Strait N
FAU - Cockerill, Alyson
AU  - Cockerill A
FAU - Munster, Pamela
AU  - Munster P
LA  - eng
GR  - R01 CA122657/CA/NCI NIH HHS/United States
GR  - R01 CA183071/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20140617
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Blood Glucose)
RN  - 0 (Glycated Hemoglobin A)
RN  - 0 (Insulin)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (hemoglobin A1c protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Biomarkers, Tumor/metabolism
MH  - Blood Glucose/analysis
MH  - Female
MH  - Follow-Up Studies
MH  - Glycated Hemoglobin/metabolism
MH  - Humans
MH  - Insulin/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/immunology/*metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Prognosis
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors
MH  - Retrospective Studies
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC5257275
MID - NIHMS605802
COIS- The authors do not have any financial support or conflicts of interest to 
      disclose.
EDAT- 2014/06/18 06:00
MHDA- 2014/10/29 06:00
PMCR- 2017/01/23
CRDT- 2014/06/18 06:00
PHST- 2014/05/14 00:00 [received]
PHST- 2014/06/03 00:00 [accepted]
PHST- 2014/06/18 06:00 [entrez]
PHST- 2014/06/18 06:00 [pubmed]
PHST- 2014/10/29 06:00 [medline]
PHST- 2017/01/23 00:00 [pmc-release]
AID - 10.1007/s00280-014-2510-0 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2014 Aug;74(2):359-65. doi: 
      10.1007/s00280-014-2510-0. Epub 2014 Jun 17.