Abstract P1-03-02: CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity
Authors: Hertz Daniel L , Snavely Anna C , McLeod Howard L , Walko Christine M , Ibrahim Joseph G , Anderson Steven , Weck Karen E , Rubin Peter , Olajide Oludamilola , Moore Susan , Raab Rachel , Carrizosa Daniel R , Corso Steven , Schwartz Gary , Peppercorn Jeffrey M , Evans James P , Desta Zeruesenay , Flockhart David A , Carey Lisa A , Irvin William J 
Published: May 2015

Abstract
Background: Tamoxifen is a selective estrogen receptor modulator that is the most commonly used and cost effective hormonal agent for pre-menopausal hormone-receptor positive breast cancer patients. CYP2D6 activity phenotype, which is classified by genotype, predicts the extent of metabolic activation of tamoxifen to endoxifen. We previously reported that increasing the daily dose to 40 mg/day in intermediate metabolizers (IMs), but not poor metabolizers (PMs), achieves target endoxifen concentrations, defined as that of extensive metabolizers (EMs) on 20 mg/day. There was substantial endoxifen variability in the IM phenotype group, which is composed of several discrete diplophenotypes (EM/IM, EM/PM, IM/IM, IM/PM). We enrolled a second, larger cohort of patients in order to determine whether these diplophenotypes should be combined into a single IM phenotype or segregated.
Methods: 380 patients on tamoxifen ≥ 4 months and not on potent CYP2D6 inhibiting medications enrolled in Lineberger Comprehensive Cancer Center (LCCC) trial 0801. Genotyping was performed using the Amplichip® CYP450 test (Roche Diagnostics) for CYP2D6, followed by systematic assignment of phenotype based on diplophenotype. Tamoxifen was increased from 20 to 40 mg/day in PMs and IMs. Endoxifen concentrations in IM diplophenotypes were compared with EM/EMs and PM/PMs at baseline and at 4 months (after dose increase in patients with IM and PM phenotypes).
Results: After exclusion of UM patients and patients missing endoxifen data at baseline and/or 4 months, 295 patients were included in this analysis. At baseline the EM/IM patients had similar endoxifen level to the EM/EM patients while the IM/IM and IM/PM patients had similar levels to the PM/PMs. After 4 months on 40 mg/day the endoxifen concentrations in EM/IM patients were significantly greater than EM/EMs; EM/PM and IM/IM patients were similar to EM/EMs; but IM/PM patients remained significantly lower than EM/EMs and similar to PM/PMs (See Table 1 for results).
Conclusions: The large group of patients currently defined as CYP2D6 intermediate metabolizers is comprised of four distinct CYP2D6 diplophentoypes. The most metabolically active diplophenotype (EM/IM) are very similar to EM/EMs while the least active diplophenotype (IM/PM) are similar to PM/PMs. A more accurate CYP2D6 activity classification system may be necessary if genetic association testing and genotype-guided therapy are pursued.
Endoxifen Level at Baseline and 4 Months by CYP2D6 Diplophenotype Baseline Endoxifen 4-Month Endoxifen DiplophenotypenMedian (SD)P-val vs. EM/EMP-val vs. PM/PMMedian (SD)P-val vs. EM/EMP-val vs. PM/PMEM/EM11038.67 (6.01)NAp=0.00018.23 (5.09)NAp=0.007EM/IM2568.02 (4.75)p=0.09p=0.00213.11 (9.38)p&lt;0.0001p&lt;0.0001EM/PM2745.72 (4.45)p=0.0001p=0.028.91 (5.28)p=0.42p=0.003IM/IM2174.29 (4.10)p=0.001p=0.266.52 (5.53)p=0.27p=0.24IM/PM2323.90 (3.17)p&lt;0.0001p=0.485.82 (3.47)p=0.0009p=0.77PM/PM3133.33 (2.89)p=0.0001NA6.08 (2.57)p=0.007NA1Diplophenotype classified as extensive metabolizer phenotype, continued on 20 mg/day. 2Diplophenotypes classified as intermediate metabolizer phenotype, changed to 40 mg/day. 3Diplophenotype classified as poor metabolizer phenotype, changed to 40 mg/day.
Citation Format: Daniel L Hertz, Anna C Snavely, Howard L McLeod, Christine M Walko, Joseph G Ibrahim, Steven Anderson, Karen E Weck, Peter Rubin, Oludamilola Olajide, Susan Moore, Rachel Raab, Daniel R Carrizosa, Steven Corso, Gary Schwartz, Jeffrey M Peppercorn, James P Evans, Zeruesenay Desta, David A Flockhart, Lisa A Carey, William J Irvin Jr. CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-02.