CYP2D6 genotype and tamoxifen response: meta-analysis of heterogeneous population

Tamoxifen treatment results in substantial inter-individual variability of outcome, possibly due to genetic variability in CYP2D6.  The clinical usefulness of CYP2D6 genotyping for prediction of tamoxifen outcome has not been established because of conflicting reports.   This controversy is well illustrated by secondary analyses from 3 large adjuvant tamoxifen trials (ATAC, BIG 1-98, and ABCSG 8), which came to different conclusions regarding the association between CYP2D6 genotype variants.  The International Tamoxifen Pharmacogenomics Consortium (ITPC) was established to aggregate the worldwide experience regarding CYP2D6 and the clinical outcomes of tamoxifen as adjuvant therapy for breast cancer. It comprises twelve research projects from nine countries and three continents that contributed clinical and genetic data for a total of 4,973 breast cancer patients treated with tamoxifen. Investigators from ITPC performed a meta-analysis on data from 4,973 tamoxifen treated patients and the result was just released in Journal Clinical Pharmacology and Therapeutics. The meta-analysis showed that “CYP2D6 poor metabolizer status was associated with poorer Invasive Disease-Free Survival (IDFS: HR=1.25; 95% CI 1.06, 1.47; P=0.009)” in patients meeting strict criterion. “However, CYP2D6 was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (Criterion 2, n=2443; 49%; P=0.25) nor when no exclusions were applied (Criterion 3, n=4935; 99%; P=0.38)”. This study demonstrates the complexity of performing a retrospective biomarker study. The lack of effect in the entire heterogeneous population highlights the need for prospective studies to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

The data used in the meta-analysis are available for download on the PharmGKB.

 --Blog post written by Li Gong

New EGFR VIP Summary Published in PG&G

The epidermal growth factor receptor (EGFR) is involved in the growth of many epithelial malignancies, such as non-small-cell lung cancer (NSCLC), pancreatic and colorectal cancer. It has therefore been a key target for the development of cancer therapeutics. These include tyrosine kinase inhibitors (gefinitib and erolinitib) and monoclonal antibodies (cetuximab and panitumumab).
   
The PharmGKB Very Important Pharmacogene (VIP) Summary for EGFR provides a concise overview of the role of EGFR as a drug target in the treatment of cancer. Key somatic and germline EGFR polymorphisms associated with drug responsiveness and acquired drug resistance are discussed.

• View the interactive EGFR VIP Summary on PharmGKB
• See FDA and EMA drug labels linked to EGFR
• View EGFR variants associated with drug response and resistance

Read the publication:
PharmGKB summary: very important pharmacogene information for the epidermal growth factor receptor. Hodoglugil U, Carrillo MW, Hebert JM, Karachaliou N, Rosell RC, Altman RB, Klein TE.
Pharmacogenet Genomics. 2013 Aug 18. (Epub ahead of print)

CPIC publishes guidelines for DPYD and fluoropyrimidines

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines for the use of genetic test results for DPYD in fluoropyrimidine dosing. The guideline in Clinical Pharmacology and Therapeutics recommends strategies for drug dosing or alternative drug choice in cancer patients who have known variants in the dihydropyrimidine dehydrogenase (DPYD) gene to avoid serious toxicity. 

DPYD is a VIP gene that encodes the enzyme for the rate limiting step in the metabolism of 5-fluorouracil (5-FU) and other fluoropyrimidines such as capecitabine (see the Fluoropyrimidine Pathway, Pharmacokinetics). DPD catalyses the conversion of 5-FU to dihydrofluorouracil (DHFU) leading to its inactivation, blockage of this route of the pathway leads to high levels of active drug metabolites and severe and sometimes fatal toxicity. Inactivating variants of DPYD such as DPYD*2A (rs3918290), DPYD*13 (rs55886062), or rs67376798 result in non-functional protein. The guideline suggests dose reduction for individuals known to be heterozygous for these inactivating variants, and avoidance of fluoropyrimidines for homozygotes of these inactivating variants. 

For details see the CPIC guideline and supplement for capecitabine, fluorouracil, tegafur and DPYD

Read the updated DPYD VIP Summary

For other CPIC guidelines see the list of CPIC publications and guidelines in progress 

 

Tamoxifen Pharmacokinetic Pathway Published

Tamoxifen, a selective estrogen receptor modulator, is used in the treatment and prevention of estrogen receptor positive breast cancer. The paper detailing the pharmacokinetic pathway of tamoxifen has been published by PG&G and can be found online. The pathway can also be found on our website. View all pathways on PharmGKB.

Read the article:
PharmGKB Summary: Tamoxifen Pathway, Pharmacokinetics
Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB & Klein TE
Pharmacogenet Genomics. 2013 Aug 18.

CYP2C8 VIP published in PG&G

CYP2C8 is a member of the cytochrome P450 family of drug metabolizing enzymes. It plays a major role in the metabolism of many commonly used drugs. Several CYP2C8 SNPs have been associated with variability in metabolism, disposition and response for drugs such as repaglinide, rosiglitazone, pioglitazone, paclitaxel, bisphosphonates, amiodarone and amodiaquine.  We have recently published the CYP2C8 pharmacogenomic summary in Journal Pharmacogenetics and Genomics.

Find out more...

View our CYP2C8 VIP on PharmGKB.

Read our new publication:
PharmGKBsummary:  very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8

View all VIPs on PharmGKB.

New PharmGKB VIP Summary: NAT2

N-acetyltransferase enzymes (NAT1 and NAT2) are involved in the metabolism and detoxification of xenobiotics. NAT2 is predominantly expressed in the liver and has a role in the metabolism of numerous therapeutic drugs including caffeine and BiDil. Genetic variants in the NAT2 gene result in a slow, intermediate or rapid acetylator phenotype.

Numerous studies have reported an association between slow acetylator status (based on NAT2 genotype) and anti-TB drug-induced hepatotoxicity, though other studies find no such association. Similarly, the association between NAT2 genetic variants and side effects of co-trimoxazole or hydralazine is also unclear.  

The PharmGKB VIP Summary for NAT2 discusses these contradictions and links to summaries of important NAT2 variants underlying these PGx associations. 

 

Tacrolimus and cyclosporine pathways published

Tacrolimus and cyclosporine are two immunosuppressants given to solid organ transplant patients to prevent allograft rejection. A PharmGKB summary discussing the pharmacokinetics, pharmacodynamics and pharmacogenetics of these two drugs has been published in Pharmacogenetics and Genomics, and is now available to read online ahead of print. The summary also includes two comprehensive pathway diagrams covering the pharmacokinetics and pharmacodynamics of the drugs.

Read the article:
PharmGKB summary: cyclosporine and tacrolimus pathways.
Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB
Pharmacogenet Genomics. 2013 Aug 5.