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© 2002 American Society for Clinical Oncology
Genetic Strategies to Individualize Supportive CareWashington University School of Medicine, Siteman Cancer Center, St Louis, MO SINCE THE INTRODUCTION of cancer chemotherapy there has been a robust effort to generate individualized treatment strategies for each patient. Measurement of patient organ function (eg, carboplatin and glomerular filtration rate), assessment of tumor biologic features (eg, estrogen receptor in breast cancer), and targeted drug administration (eg, hepatic arterial infusion for liver metastasis) have all been incorporated into standard practice. This quest for individualized therapy has taken a step forward with the introduction of trastuzumab and imatinib, therapies that are targeted to tumors with amplified her-2 or alterations in c-kit or BCR/ABL, respectively.1,2 Recently, gene expression arrays have been used in the molecular classification of disease, highlighting the great genetic heterogeneity among cells with histologically similar appearance. An example of the impact of characterized gene expression has been shown with diffuse large B-cell lymphoma (DLBCL). By using a gene expression array containing 17,856 genes which are preferentially expressed in lymphoid cells, investigators have demonstrated the presence of two molecularly distinct forms of the disease: germinal center B-like DLBCL and activated B-like DLBCL.3 Importantly, patients with germinal center B-like DLBCL had a superior overall survival compared with those with activated B-like DLBCL, with a 5-year survival of 76% versus 16%, respectively.3 The use of unconstrained analysis of gene transcripts is rapidly expanding to identify other areas of oncology where tumor RNA "signatures" are able to better ascertain patients who would benefit from individualized treatment approaches. The human genome is also an important source of variation in clinical phenotype. Current estimates place more than 3,000,000 single nucleotide polymorphisms (SNPs) throughout an individual’s DNA.4 Whereas SNPs account for the majority (> 90%) of genetic variants, dinucleotide repeats and other DNA abnormalities are also observed. Pharmacogenetics, the hereditary basis for interindividual differences in drug effect, takes advantage of the emerging SNP data to predict those patients at risk for extreme toxicity and, more recently, altered efficacy after chemotherapy. SNPs in thiopurine methyltransferase and dihydropyrimidine dehydrogenase have been associated with altered drug metabolism and elevated risk of severe toxicity from mercaptopurine and fluorouracil, respectively.5-7 A variant number of dinucleotide repeat sequences (range, 5 to 8 repeats) in the promoter for UDP-glucuronosyltransferase 1A1 has an influence on in vitro and in vivo glucuronidation of SN-38, the active metabolite of irinotecan.8 Patients with seven repeat sequences have a four-fold relative risk of experiencing severe toxicity compared with patients with six repeat sequences, including grade III/IV diarrhea and neutropenia.9,10 Genetic variation has also been shown to be associated with response to chemotherapy. An initial study of response to paclitaxel in non–small-cell lung cancer found no objective responses in patients with ß-tubulin gene mutations, compared with a response rate of approximately 40% in patients without mutations.11,12 The presence of three copies of a 28-base pair repeat sequence in the thymidylate synthase promoter enhancer region has also been associated with lower response from fluorouracil therapy in metastatic colorectal cancer,13,14 adjuvant colon cancer,15 and neoadjuvant rectal cancer,16 when compared with patients with two copies of the repeat sequence. Together, these examples highlight how the prospective knowledge of a patient’s genotype status may permit patient-specific therapy that may reduce the risk of acute toxicity from chemotherapy, while enhancing therapeutic benefit.
With supportive care providing such a critical component of patient management, it is not surprising that genetics may influence this area as well. In this issue, Kaiser et al17 detail the impact of patient genotype for the cytochrome P-450 enzyme 2D6 (CYP2D6) on the ability of ondansetron and tropisetron to prevent nausea and vomiting after chemotherapy. This enzyme is responsible for degradation of these drugs, as well as other 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists.18 CYP2D6 mutations or deletions occur in However, this study offers only a first look at the application of pharmacogenetics to supportive care, with the study having many limitations for translation into clinical management. Patients received chemotherapy agents with a wide variation in emetogenic potential, and patients receiving opioids were excluded from participation.17 In addition, 56% of patients received concomitant glucocorticoids and only 56 (21%) of 270 received a platinum-containing regimen. These factors, combined with the use of two different 5-HT3 receptor antagonists, caution the use of pharmacogenetically directed therapy based on this study alone. The integration of pharmacogenetics into other areas of supportive care is not far behind. Polymorphisms in the UGT2B7 gene appear to have predictive power for morphine disposition.23 Pharmacogenetic profiling of bacterial isolates is now being evaluated to guide the selection of antimicrobial therapy.24 The recently described SNPs in the genes encoding erythropoietin and colony-stimulating factors may even lead to an influence of pharmacogenetics in hematopoietic supportive care.25,26 There are still a number of obstacles to overcome before pharmacogenetic testing is a common component of medical decision-making in oncology. One major area is defining risk/benefit for genetic testing. Concerns over genetic discrimination are primarily theoretical, but they need to be addressed through sound legislation and strong moral fiber. Most pharmacogenetic targets are not likely to be important predictors of disease susceptibility or risk. However, CYP2D6 has been associated with a patient’s risk of bladder and lung cancer and Parkinson’s disease; this information may identify a patient and, of greater relevance, a family that may represent a higher insurance risk.27-29 There is now a need to quantitate the level of benefit that pharmacogenetics will bring to patients. In the study by Kaiser et al,17 50 patients needed to be studied so that one patient could benefit from genetic testing for selection of antiemetic therapy. Is a 1:50 benefit ratio enough to make genotyping worthwhile? From a financial standpoint there may be no gain from such tests, as one could simply use an alternate antiemetic regimen in the next course of chemotherapy. Clinically, there could be a big gain to helping any patient avoid side effects. What is needed now is clear evidence of the ways in which genotype analysis can be of clinical benefit. This means the early inclusion of pharmacogenetics into clinical trials and the prospective assessment of pharmacoeconomics and related issues. Only then can the value of pharmacogenetics be clearly seen and integrated into its place as a tool to individualize patient care. ACKNOWLEDGMENTS Supported in part by grant no. 1P30CA091842 from the Siteman Cancer Center and grant no. 1U01 GM63340 from the Pharmacogenetics Research Network. REFERENCES
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Savage DG, Antman KH: Imatinib mesylate: A new oral targeted therapy. N Engl J Med 346: 683-693, 2002 3. Alizadeh AA, Eisen MB, Davis RE, et al: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403: 503-511, 2000[CrossRef][Medline] 4. McLeod HL, Evans WE: Pharmacogenomics: Unlocking the human genome for better drug therapy. Annu Rev Pharmacol Toxicol 41: 101-121, 2001[CrossRef][Medline] 5. McLeod HL, Krynetski EY, Relling MV, et al: Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14: 567-572, 2000[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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10% of the general population and have been associated with a poor metabolizer (PM) phenotype.
