Personalized Medicine: Real Clinical Examples! April 25, 2008

There are more than 60 articles in the personalized medicine category on my blog and I have a page dedicated to this emerging field of medicine. I also wrote a summary about it. But now it is time to show you some real examples; some cases and ideas that could play a major role in the future of healthcare. Genetic tests and pharmacogenetic variants which are used in clinical practice or will be used soon. I would like to consider this post as a continuously developing collection or database of examples and ideas. Please let me know if you know other examples of personalized medicine that were published in a peer-reviewed journal.

• Azathioprine (AZA) and 6-mercaptopurine (6- MP) in inflammatory bowel disease¹:

Thiopurine S-methyltransferase (TPMT) is a key metabolic enzyme for azathioprine (AZA) and 6-mercaptopurine (6- MP), 2 widely used medications in the treatment of IBD. AZA is metabolized to 6-MP and subsequently 6-thioguanine (6-TG), the active metabolite. 6-MP can be inactivated by either TPMT or xanthine oxidase to nontoxic products. SNPs in the TPMT gene reduce TPMT activity, shunting metabolism to 6-TG and increasing toxicity, particularly neutropenia; TPMT deficiency can serve to lower the starting dose or to alternative therapies. TPMT enzyme (phenotype) activity in red blood cells and genotype testing to detect the major mutations that lower TPMT activity are both available and used by most physicians in the United Kingdom, including 75% of gastroenterologists. Approved by the US Food and Drug Administration (FDA), TPMT testing has led to relabeling for AZA and 6-MP to provide genomic information to providers.

• Methotrexate in Crohn’s disease¹:

This pharmacogenetic test is used in IBD treatment. The SNPs of methylenetetrahydrofolate reductase (MTHFR) are associated with increased toxicity of methotrexate used to treat Crohn’s disease.

• Her2/neu positivity in breast cancer²:

HER2/neu is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor.

Human epidermal growth factor receptor 2-overexpressing breast cancer is known to be associated with particularly aggressive disease and poor prognosis. On the other hand, human epidermal growth factor receptor 2/neu overexpression may predict response to endocrine therapy or chemotherapy. Nevertheless, trastuzumab increases the clinical benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress human epidermal growth factor receptor 2. In the pretrastuzumab era, retrospective analyses have shown that human epidermal growth factor receptor 2 overexpression is an adverse prognostic factor associated with an increased risk of disease recurrence and death. In the trastuzumab era, this drug has changed the natural history of human epidermal growth factor receptor 2-positive breast cancer, either in the metastatic or, according to the most recent evidences, in the adjuvant setting.

• VKORC1 and CYP2C9 polymorphisms in warfarin metabolism³:

Warfarin is the most widely prescribed oral anticoagulant, but there is greater than 10-fold interindividual variability in the dose required to attain a therapeutic response. Pharmacogenetic analysis of two genes, the warfarin metabolic enzyme CYP2C9 and warfarin target enzyme, vitamin K epoxide reductase complex 1 VKORC1, confirmed their influence on warfarin maintenance dose. Possession of CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, is associated with a significant decrease in the mean warfarin dose. Several single nucleotide polymorphisms (SNPs) in VKORC1 are associated with warfarin dose across the normal dose range. Haplotypes based on these SNPs explain a large fraction of the interindividual variation in warfarin dose, and VKORC1 has an approximately three-fold greater effect than CYP2C9. Algorithms incorporating genetic (CYP2C9 and VKORC1), demographic, and clinical factors to estimate the warfarin dosage, could potentially minimize the risk of over dose during warfarin induction.

FDA approved it last year.

• CYP2C19 polymorphism in Helicobacter pylori–related disorders¹:

The treatment of H pylori infection requires a multidrug regimen that contains multiple antibiotics plus proton pump inhibitors (PPIs) or histamine-2 receptor blockers for eradication. Pharmacogenetic studies have revealed potentially important host genetic variability to PPI response; CYP2C19 SNPs define patients as rapid (RM), intermediate (IM), or poor metabolizers (PM). Asian populations demonstrate a higher frequency of PMs, higher PPI efficacy, and may have better H pylori eradication at standard doses. With omeprazole the most sensitive to CYP2C19 variation, H pylori eradication rates may vary with specific PPIs and are generally lower; higher PPI doses may be needed in RMs. Pretreatment PPI genotyping improves H pylori eradication rates but cost effectiveness has not yet been studied.

• UGT1A1 polymorphism in irinotecan treatment of colon cancer¹:

Irinotecan, a topoisomerase I inhibitor, is a first-line treatment for colon cancer, alone or in combination. Delivered as a prodrug, irinotecan must be metabolized to SN-38, an active compound that is then inactivated by UDP glucuronosyltransferases (UGTs). Variability in one of these enzymes, UGT1A1, leads to accumulation of SN-38 and increased toxicity, most notably neutropenia and diarrhea. Specific UGT1A1*28 and UGT1A1*6 (in Asians) SNPs markedly increase irinotecan toxicity risk. Further, Gilbert’s syndrome, a benign disorder of indirect hyperbilirubinemia, is caused by the same mutations and predicts irinotecan toxicity. The FDAhas relabeled irinotecan and approved tests for UGT1A1*28 SNPs; UGT1A1*6 analysis will be additionally needed for Asian patients. UGT1A1 testing may prevent severe irinotecan toxicity through dose reduction or switching to an alternative oxaloplatin-based regimens. For oxaloplatin, genetic testing for SNPs in the DNA repair genes XRCC1, ERCC1, and ERCC2 and glutathione-S-transferase (GST), predict better response, although diagnostic tests for these mutations are not yet routinely available.

• Polymorphism of 5-fluorouracil in the treatment of gastric cancer¹:

Even with the arrival of new biologic agents against colon cancer, 5-fluorouracil (5-FU) remains a mainstay of treatment but carries a high risk of adverse effects. Multiple SNPs in DPYD decrease DPY enzyme activity, which would normally inactivate 5-FU and its orally administered prodrug capecitabine; heterozygotes for these genetic variants reach a prevalence of 3%–5%. Cost effectiveness will determine the usefulness of DPD enzyme assays or genotype testing for DPYD variants prior to using 5-FU or capecitabine. In addition, genetic variants in the thymidylate synthase promoter lead to decreased tumor response to 5-FU–based regimens. Pharmacogenetic lessons learned in colon cancer treatment seem to apply to gastric cancer.

References:

1. Patel KK, Babyatsky MW. Medical Education: A Key Partner in Realizing Personalized Medicine in
   Gastroenterology. Gastroenterology. 2008 Mar;134(3):656-61.
2. Ferretti G, Felici A, Papaldo P, Fabi A, Cognetti F. HER2/neu role in breast cancer: from a prognostic foe to a predictive friend. Curr Opin Obstet Gynecol. 2007 Feb;19(1):56-62.
3. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 – rationale and perspectives. Thromb Res. 2007;120(1):1-10. Epub 2006 Dec 11.