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Impact of PGx on Chemotherapy

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Vol. 18 • Issue 11 • Page 12
Molecular Edge

Traditionally, pharmacogenetics involves the study of genetic variation in metabolism of drugs and toxins. The concept of phamacogenetics has been widened to encompass how genetic alterations central to the development of diseases may be used to target medical treatment in a patient-tailored way (i.e., personalized medicine).

Pharmacogenetics can define both predictive and prognostic factors. Predictive factors help identify patients who will benefit from a specific treatment, allowing appropriate chemotherapy with the most benefit. Prognostic factors are associated with overall outcome, independent of treatment, and are useful in identifying patients at high risk for tumor recurrence who may ultimately benefit from additional therapy. Choosing the correct therapy for the patient becomes critical for improving clinical outcomes, avoiding unnecessary toxicities and reducing costs of clinical care.

Colorectal Cancer

UGT1A1

Irinotecan (Camptosar® Pfizer Pharmaceuticals) is a topoisomerase I inhibitor shown to prolong survival in metastatic colorectal cancer (mCRC) patients. The uridine-diphosphoglucuronosyltransferase 1A1 gene (UGT1A1) encodes specific enzymes capable of inactivating SN-38, the active metabolite of irinotecan. Some individuals express decreased levels of these enzymes due to single nucleotide polymorphisms (SNPs) in the UGT1A1 promoter region.

One SNP, called the *28 variant (*1 is the wild type), is common in the U.S. Caucasian population. Persons with UGT1A1 *1/*28 and UGT1A1*28/*28 genotypes have significant risk for irinotecan toxicity. Patients with UGT1A1*28, especially those who inherit two copies, may demonstrate variable drug response and adverse effects such as severe diarrhea and severe neutropenia. A sensitive pharmacogenomic screen may reduce healthcare costs for select patients by enhancing therapeutic benefits and reducing the incidence of adverse reactions to a variety of drugs, including irinotecan.

While the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group supports the rationale, analytic validity and clinical validity of UGT1A1 genotyping, EGAPP found that there is not sufficient evidence to recommend routine testing for UGT1A1 polymorphisms in patients with metastatic colorectal cancer with the intent to avoid adverse drug reactions.

Other issues, such as patient preferences and tumor response, may impact the implementation of UGT1A1 genotyping. The cost of UGT1A1 genotyping is relatively low in the context of cancer treatment; however, the full utility of UGT1A1 genotyping remains to be determined.

DPYD

5-Fluorouracil (5-FU or f5U; Adrucil® Fluorouracil® Efudex® Fluorplex® is a pyrimidine analog that disrupts the proper synthesis of nucleotides used in DNA synthesis and repair. It is commonly used in the treatment of various cancers. 5-FU/ Capecitabine (its oral prodrug) is used in the first-line treatment of colon cancer. 5-FU is normally metabolized (degraded) by dihydropyrimidine dehydrogenase (DPYD), but genetic variants of DPYD reduce 5-FU metabolism to varying degrees, resulting in dramatic increases in effective 5-FU dose in patients carrying the variants. As a result, approximately 30 percent of patients treated with 5FU/Capecitabine develop a significant toxic response. Genetic variants in other genes, including thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR), may also influence 5FU/Capecitabine response. Pre-therapeutic SNP analysis may help define a panel of mutations useful in screening 5FU/Capecitabine candidates to minimize severe toxicity, reduce patient morbidity and increase cost efficiency.

KRAS

Treatments for patients with colorectal cancer include several targeted monoclonal antibodies as well as conventional chemotherapeutic agents. Bevacizumab (Avastin®, cetuximab (Erbitux® and panitumumab (Vectibix are some of the most common monoclonal antibodies used to treat mCRC patients. Both cetuximab and panitumumab interact with epidermal growth factor receptor (EGFR) and are known as anti-EGFR drugs. A differential response to anti-EGFR antibody therapy has been observed based on mutational status of an oncogene called KRAS. mCRC patients with a mutation in KRAS are much less likely to respond to anti-EGFR therapy and have a shorter survival than those patients with a normal (wild type) KRAS gene. It is suggested that KRAS mutations can be detected in up to 45 percent of colorectal cancers. The National Comprehensive Cancer Network (NCCN) recently amended its clinical practice guidelines to include KRAS mutation analysis for all patients with mCRC.

Breast Cancer

Cytochrome P450 2D6 (CYP2D6) is an enzyme found primarily in the liver that is involved in the metabolism of "Xenobiotic" various drugs and chemicals. Expression of the CYP2D6 gene varies considerably between individuals due to the presence of various genetic polymorphisms. Ethnicity is a factor in the occurrence of CYP2D6 variability. This variability is accounted for by the differences in the prevalence of various CYP2D6 genetic variants. Caucasians, African Americans and Asians possess different CYP2D6 variants that impact the metabolic functions of CYP2D6.

Such variants of CYP2D6 can influence the outcome of tamoxifen treatment of women with estrogen receptor-positive breast cancer. Women who are "poor metabolizers" of tamoxifen (i.e., have little or no functioning CYP2D6) generally have a poor outcome as compared to wild-type carriers due to an inability to metabolize tamoxifen sufficiently to its therapeutic metabolite, endoxifen. Patients with other variant forms of the gene CYP2D6 or who use medications that inhibit the enzyme may also receive reduced benefit.

Identifying patients carrying the "poor metabolizer" polymorphism may cause treatment regimens to be modified and/or alternate therapy to be considered. Other treatment options for estrogen receptor-positive breast cancer exist, but tamoxifen remains the most common endocrine therapy administered worldwide to women with estrogen receptor-positive breast cancer because of lower cost and toxicity. Patients with a high risk of progression of breast cancer despite tamoxifen treatment can be identified and notified about the higher risk or treatment failure as a basis to justify the more costly and toxic alternative treatments.

While the data are in favor of CYP2D6 genotypes as a predictor of response to tamoxifen, additional studies are necessary to recommend testing to all breast cancer patients contemplating tamoxifen treatment. In October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about the sub-therapeutic effects of this specific polymorphism.

Further Investigation

The role of pharmacogenetics in clinical medicine is attracting a significant amount of attention within various specialties, particularly oncology. However, cancer is a heterogeneous disease and the utility of these genomic applications within the subspecialties for routine clinical testing warrants more investigation.

As with all pharmacogenetic testing, disadvantages remain. For example, individuals testing negative for specific polymorphisms may develop a false sense of assurance that select treatment will work for them. Conversely, genotyping results may dissuade patients from therapy regimens that may be beneficial. Professional societies representing the practice of genetics and molecular pathology are actively working toward establishing standard policies, protocols and functional clinical algorithms that will hopefully bring more widespread acceptance of pharmacogenetic testing.

Dr. Nordberg is associate professor, Departments of Pathology and Pediatrics; director, Molecular Pathology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport; and Head of the Web Editorial Committee for the ­Association of Molecular Pathology.




     

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