Pharmacogenetics of solid tumors: directed therapy in breast, lung, and colorectal cancer: a paper from the 2008 william beaumont hospital symposium on molecular pathology.
Genetic variability in drug-metabolizing enzymes and signaling pathways affects chemotherapy-related toxicity and treatment outcome in cancer. In breast and colorectal cancer, polymorphisms in metabolic enzymes involved in tamoxifen and irinotecan therapies has led the U.S. Food and Drug Administration to address genetic factors relevant to patient consideration of treatment with these compounds. Tamoxifen therapeutic failure in breast cancer has been associated with reduced CYP2D6 activity due to inefficient activation of tamoxifen. Irinotecan toxicity in colorectal cancer is more common in patients with reduced-activity UGT1A alleles, resulting in excessive exposure to the potent SN-38 metabolite. In colorectal and lung cancers, somatic mutations in the epidermal growth factor receptor and downstream signaling molecules have been associated with the therapeutic outcome of epidermal growth factor receptor-directed therapies. This review discusses the current knowledge regarding the utility of single gene-UGT1A1, CYP2D6, EGFR, and KRAS-or multigene analysis, for optimizing breast, colorectal, and lung cancer therapy. Current advances in these areas highlight how pharmacogenetics help personalized decision-making for patient management.
Snozek
Christine L H
CL
Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
O'Kane
Dennis J
DJ
Algeciras-Schimnich
Alicia
A
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D010597:Pharmacogenetics / Q000379:methods*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D013629:Tamoxifen / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000099148:UGT1A1 Enzyme
D019389:Cytochrome P-450 CYP2D6; D066246:ErbB Receptors; D014453:Glucuronosyltransferase; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D013629:Tamoxifen; D018631:ras Proteins; D000099148:UGT1A1 Enzyme; C117307:KRAS protein, human; C512478:EGFR protein, human