CANCER DRUG SENSITIVITY
Alpha Genomix Oncology Report
The Alpha Genomix Oncology Report provides patient-specific, evidence-based information specifically including genes related to chemotherapy treatments. This report delivers dosing guidance for currently affected medications, additional risk factors and a listing of all potentially risk-related medications – including anticancer therapies to assist clinicians in determining the most safe and effective medication and dose well into the future.
The CYP2B6 is responsible for the metabolism of 4% of the top 200 prescribed including those used for cancer treatment, such as Cyclophosphamide, Doxorubicin and fludarabine. A large number of variants have been reported. The CYP2B6 assay identifies some common variants associated with variability in CYP2B6 enzyme activity and in turn patient’s response to treatment.
The CYP2C19 is involved in the metabolism of approximately 10% of clinically relevant medications including drugs used during cancer therapy such as Ondansetron, Patients with CYP2D6 extensive, intermediate or poor metabolizer genotypes are more likely to have an increased response to ondansetron as compared to those with CYP2D6 ultrarapid metabolizer genotypes. This increased response leads to a reduced risk of vomiting after chemotherapy or anesthesia.
The CYP2D6 is involved in the metabolism of 25% of clinically important medications included those used for cancer treatment such as Tamoxifen. To date more than a 100 different variants have been identified. The CYP2D6 assay identifies common variants associated with variability in CYP2D6 enzyme activity.
CYP3A4 and 3A5 are involved in the metabolism of approximately 50% of commonly prescribed drugs including ones used to treat cancer such Docetaxel, Paclitaxel, Cyclophosphamide, Teniposide, Doxorubicin, Etoposid, Tipifarnib and Fluorouracil. CYP 3A4 and CYP3A5 enzymes have overlapping substrate specificity and the contribution of CYP3A5 in the overall metabolism is smaller than the one for CYP3A4. The CYP3A assay tests for the presence of CYP3A genetic variants that can influence its activity and in turn patients response to treatment.
Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of various cancer therapies such as Mercaptopurine, Azathioprine, cisplatin, Azathioprine, thioguanine, and cyclophosphamide. Genetic variations have been identified and were shown to influence that activity of TPMT enzymatic activity and accordingly it was shown that 88.6% of people had high enzyme activity, 11.1% had intermediate activity and 0.3% had undetectable activity. The TPMT assay tests for the presence of TMPT variation that influence the enzyme’s activity.
Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) main functions lie within the liver, where it is the sole enzyme responsible for the metabolism of Bilirubin, the Hydrophobic breakdown product of Heme catabolism. In addition, UGT1A1 is involved in the metabolism of cancer drugs such as Etoposide, Irinotecan and Raloxifene. UGT1A1 is inhibited by drugs such as Atazanavir, Indinavir and Tranilast. To date, 113 different UGT1A1 variants have been described. These variants can confer reduced or increased activities, as well as inactive or normal enzymatic activity. The UGT1A1 assay tests for variants that can influence the enzymatic activity of UGT1A1.
The UGT2B15 are of major importance in the elimination of potentially toxic compounds. It has been implicated in the metabolism of chemotherapeutic drugs including tamoxifen. The UGT2B15 assay tests for variants that can influence the enzymatic activity of UGT2B15 which in turn determine patient’s response to certain chemotherapies.
DPYD is the initial and rate limiting enzyme in the three step pathway of uracil and thymidine catabolism and the pathway leading to the formation of beta-alanine. The DPYD protein is responsible for the metabolism of various chemotherapeutic agents including 5-Fluorouracil (5FU), Capecitabine, and Tegafur. Decreased DPYD activity is associated with a greater than four-fold risk of severe or fatal toxicity from standard doses of 5FU. The DPYD assay tests for the presence of DPYD mutations associated with decreased DPYD activity.
The CYP2C9 is involved in the metabolism of 15% of clinically important medications including those used for cancer treatment such as Tamoxifen. To date 30 different variants of CYP2C9 have been identified. The CYP2C9 assay identifies some common variants associated with variability in CYP2C9 enzyme activity and in turn patient’s response to certain medications.