CYP2D6 (Cytochrome P450 Family 2 Subfamily D Member 6)

CYP2D6-drug pairs were reported across four therapeutic areas (analgesia [n = 21], psychiatry [n = 17], oncology [n = 7], gastroenterology [n = 6]) with the two most researched drugs being codeine (n = 21) and tramadol (n = 18). Six (6) of 25 articles reported PGx clinical outcomes, considered to be a "measurable change in symptoms, overall health, ability to function, quality of life, or survival outcomes" in relation to PGx testing. Special EHR and claims data considerations for future work include but are not limited to addressing inconsistent phenotype categorizations (i.e., natural genotype versus phenoconversion); lack of reliable racial, ethnic, and genetic ancestry data within EHR and claims data sources; and data inoperability issues between PGx test results and EHRs.

Tamoxifen remains a primary therapeutic agent for premenopausal HR-positive breast cancer patients, and its efficacy is influenced by polymorphisms in the CYP2D6*10. It is recommended that for breast cancer patients carrying the CYP2D6 CT and TT genotypes, endometrial monitoring should be strengthened during treatment with tamoxifen, and the medication should be adjusted in a timely manner.

In conclusion, our mono-CYP CHO model confirmed the essential role of CYP2D6 in synthesizing the active TAM metabolite endoxifen and indicated that CYP2D6 is also involved in producing the by-metabolite N,N-didesmethyltamoxifen. The differences in metabolite spectra between the two mono-CYP models highlight the CYP specificity and sensitivity of our in vitro system.

The outcome of the sensitivity analysis and reverse MR analysis corroborated the findings. These findings suggested a causal relationship between BC and meningioma, and identified potential target genes associated with meningioma, which was beneficial to early identification and prevention of meningioma risk.

Transcriptional regulation of CYP2D6 expression may contribute to differences in drug response and risk for CYP2D6 phenoconversion. Efforts to understand the role of gene expression to predict CYP2D6 phenoconversion may inform the use of PGx testing in the clinical setting.

13% of the patients had an actionable phenotype and prior exposure to an impacted medication. These findings suggest a potential roadmap for improvement of medication prescription in PPC using PGx guidelines in routine clinical practice.

In this pilot study with limited sample size, CYP2D6 normal and IM metabolizer status was not associated with effectiveness or moderate-severe AEs to fesoterodine fumarate. The proportion of poor metabolizers was low; thus, further investigation in this population is warranted.

We did not observe significant associations between CYP2D6 metabolizer status or endoxifen with PFS. Small sample sizes and barriers to adequate samples in this trial prohibited determination of relationship between these markers and PFS.

We found it likely that many of these mutations would alter enzyme function, leading to changes in drug metabolism in the tumor. We provide a basis for predicting the likelihood of a patient carrying these mutations to identify patients who may benefit from a precision medicine approach to drug selection and dosing.

Moreover, in patients on tamoxifen therapy, 4-OH-solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6-interacting medications. Accordingly, 4-OH-solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen.

Sri Lankans are likely to show lower toxicity risk with sorafenib (rs7557402 c.84,131 C > G) and, higher toxicity risk with fluoropyrimidines (rs56038477 c.1236G > A) and mercaptopurine (rs116855232 c.415 C > T), and reduced effectiveness with tamoxifen (rs1065852 c.100 C > T) and platinum compounds (rs25487). These findings highlight the potential contribution of these genetic variations to the individual variability in anti-cancer dosage requirements among Sri Lankans.

In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2-21.1; rs6790761, OR 18.2, 95% CI: 15.5-21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene.