Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups

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 concentration, 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).

High prevalence of CYP2D6 ultrarapid metabolizers in a mestizo Colombian population in relation to Hispanic mestizo populations

Background: Interethnic differences in CYP2D6 allele frequency have been demonstrated across Latin–American countries. Only one previous study describing CYP2D6 genotypes in Colombian population has been performed. Thus, this study aimed to evaluate the CYP2D6 genetic variability in a mestizo Colombian population, as well as the similarities and differences concerning other Hispanic mestizo (HM) populations. Methodology: Two hundred and twelve unrelated healthy Colombian subjects were studied, in which different CYP2D6 polymorphisms were analyzed by extra long-PCR and real-time PCR. Results & discussion: A high percentage of ultrarapid metabolizers (18.4%) was found, representing the highest frequency calculated within the HM populations studied. However, the percentage of poor metabolizers (4.7%) was similar to those previously reported in HM populations.

Supportive care medications (SCMs) and pharmacogenomics (PGx) relevance in 6,985 cancer patients (pts) undergoing distress screening.

11592 Background: SCMs are prescribed based on symptom burden, but response is variable, possibly due to PGx. We investigated the association between symptom burden, SCM prescribing, and frequency of SCMs with PGx evidence. Methods: Cancer pts ≥ 18 years old and completing electronic distress screening within 90 days of intake between 1/1/2017-12/31/2017 were included. Anxiety was measured using Generalized Anxiety Disorder 2-item (0-6) and depression using Patient Health Questionnaire-2 (0-6). Fatigue, nausea, neuropathy, pain and sleep were measured on a 0-10 scale. SCM prescribing within 90 days of intake was documented. Logistic regression compared symptom scores and SCM prescribing. Receiver Operating Characteristics analysis estimated sensitivity/specificity. Optimal symptom thresholds were selected according to Youden’s J statistic. SCMs with PGx evidence level A or B (according to Clinical Pharmacogenetics Implementation Consortium) were summarized. Results: Of 6985 pts, 65% were female, 75% Caucasian, 20% African American and median age was 60. 49% reported ≥ 1 severe symptom, which correlated with SCM prescribing (p < 0.001). 3208 (46%) were prescribed SCM(s), mainly for pain (69%) or nausea (46%). Of these, 2759 (86%) received ≥ 1 SCM with PGx evidence and 2695 (84%) received a SCM metabolized by CYP2D6 - hydrocodone (47%), ondansetron (41%), and oxycodone (28%). Based on reported CYP2D6 allele frequencies conferring altered metabolism (~20%), 539 of the 2695 pts may have altered drug response. Threshold scores for each symptom are summarized in the table. Fatigue and nausea were not associated with SCM prescribing. Conclusions: Symptom burden is high in cancer pts and correlates with SCM prescribing. Many SCMs have PGx evidence, suggesting preemptive testing, particularly for CYP2D6, may have broad applicability in this population.[Table: see text]

CYP2D6 allele distribution in Macedonians, Albanians and Romanies in the Republic of Macedonia

CytochromeP450 2D6(CYP2D6) is an enzyme of great importance for the metabolism of clinically used drugs. More than 100 variants of theCYP2D6gene have been identified so far. The aim of this study was to investigate the allele distribution ofCYP2D6gene variants in 100 individuals of each of the Macedonian, Albanian and Romany population, by genotyping using long range polymerase chain reaction (PCR) and a multiplex single base extension method. The most frequent variants and almost equally distributed in the three groups were the fully functional alleles*1and*2. The most common non functional allele in all groups was*4that was found in 22.5% of the Albanians. The most common allele with decreased activity was*41which was found in 23.0% of the Romany ethnic group, in 11.0% of the Macedonians and in 10.5% of the Albanians. Seven percent of the Albanians, 6.0% of the Romani and 4.0% of the Macedonians were poor metabolizers, while 5.0% of the Macedonians, 1.0% of Albanians and 1.0% of the Romanies were ultrarapid metabolizers. We concluded that theCYP2D6gene locus is highly heterogeneous in these groups and that the prevalence of theCYP2D6allele variants and genotypes in the Republic of Macedonia is in accordance with that of other European populations.

Comprehensive CYP2D6 genotyping in a multiracial U.S. breast cancer population

553 Background: CYP2D6 genotyping has been suggested to avoid suboptimal responses to tamoxifen (T). Most studies to date are in white patients (pts) and focus on a limited number of genetic variants. In this clinical trial, we comprehensively examined CYP2D6 allele frequencies in women of heterogenous ethnicity taking tamoxifen (T). Methods: In LCCC 0801, pts on T ≥ 4 months and not on potent CYP2D6 inhibiting medications were genotyped using the CYP450 AmpliChip for 2D6 alleles: *1-*11, *15, *17, *19, *20, *29, *35, *36, *40, *41, *1XN, *2XN, *4XN, *10XN, *17XN, *35XN and *41XN. T dose was increased in pts with any intermediate or poor metabolizing (IM or PM) alleles [but not in pts homozygous for extensive metabolizing (EM) alleles]. Serial T metabolite levels are being assessed. Here we report the allele frequency data from this study compared to previously published cohorts. Results: 108 pts participated in the study: 24 (22%) African-Americans (AA), 76 (70%) non-Hispanic whites, 4 Asians, 3 Hispanics and 1 Spanish European. Genotyping revealed 28 (26%) EM/EM, 1 EM/UM (ultra-rapid), 29 (27%) EM/IM, 22 (20%) EM/PM, 8 (7%) IM/IM, 10 (9%) IM/PM, 9 (8%) PM/PM and 1 unknown. Conclusions: Pts in this trial had a similar frequency of PM alleles to previous reports, however a high proportion of pts have IM alleles. In particular, the majority (79%) of AA pts possess at least one variant allele. Since PM and IM genotypes have been associated with reduced T metabolism, this may have implications for T efficacy and emphasizes the importance of trials examining CYP2D6 genotyping as a determinant of T use. (Supported by Laboratory Corporation of America, Roche Diagnostics, NC UCRF, NCI SPORE.) [Table: see text] [Table: see text]