TY - JOUR
T1 - Computational treatment simulations to assess the need for personalized tamoxifen dosing in breast cancer patients of different biogeographical groups
AU - Mueller-Schoell, Anna
AU - Michelet, Robin
AU - Klopp-Schulze, Lena
AU - van Dyk, Madelé
AU - Mürdter, Thomas E.
AU - Schwab, Matthias
AU - Joerger, Markus
AU - Huisinga, Wilhelm
AU - Mikus, Gerd
AU - Kloft, Charlotte
PY - 2021/5/2
Y1 - 2021/5/2
N2 - Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (CSS,min ENDX) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower CSS,min ENDX. In the Women’s Healthy Eating and Living (WHEL) study proposing the target con-centration, 20% of patients showed subtarget CSS,min ENDX at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget CSS,min ENDX in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget CSS,min ENDX at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget CSS,min ENDX. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget CSS,min ENDX).
AB - Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (CSS,min ENDX) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower CSS,min ENDX. In the Women’s Healthy Eating and Living (WHEL) study proposing the target con-centration, 20% of patients showed subtarget CSS,min ENDX at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget CSS,min ENDX in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget CSS,min ENDX at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget CSS,min ENDX. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget CSS,min ENDX).
KW - Breast cancer
KW - CYP2D6
KW - Genotype
KW - Individualized dosing
KW - Model-informed precision dosing
KW - Personalized dosing
KW - Polymorphism
KW - Tamoxifen
UR - http://www.scopus.com/inward/record.url?scp=85105880022&partnerID=8YFLogxK
U2 - 10.3390/cancers13102432
DO - 10.3390/cancers13102432
M3 - Article
AN - SCOPUS:85105880022
VL - 13
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 10
M1 - 2432
ER -