Table 1.
Summary of the recommendations provided in CPIC and DPWG guidelines for drugs employed in oncology
| Drug | Gene | SNP | Reference genotype | Risk genotype | Guideline recommendation |
|---|---|---|---|---|---|
| Azathioprine, Mercaptopurine, Thioguanine# | CPIC[17-19] | ||||
| TPMT | rs1800462 rs1800584 rs1142345 rs1800460 |
CC CC TT CC |
CG, GG CT, TT TC, CC CT, TT |
Any Heterozygote, including 1/*3A (both risk variants located in the same allele): Consider a reduction starting at 30%-80% of the normal starting dose (if normal starting dose is equal or higher than 75 mg/m2/day, or equal or higher than 1.5 mg/kg/day in Mercaptopurine, and 2-3 mg/kg/day in Azathioprine). In the case of Thioguanine, start with 50%-80% of normal dose if it is equal or higher than 40-60 mg/m2/day. Allow 2-4 weeks to reach steady state after each dose adjustment Any Homozygote, plus multiple heterozygotes in *2, *3B and *4, that is an individual carrying two functional alleles: Consider alternative agents. If not possible, start with a daily dose reduction 10 times and three times a week. Adjust the dose according to the degree of myelosuppression and the specific patterns of the disease. Allow 4-6 weeks to reach a steady state after each dose adjustment For CT follow the same recommendation as for Heterozygotes in TPMT. For TT, follow the same recommendation as for TPMT Homozygotes, except for Thioguanine, where the reduction should be to 25% DPWG[6] Any Heterozygote: Select alternative drug or reduce dose by 50%. Increase dose in response of hematologic monitoring efficacy Homozygotes or combination of two or more Heterozygotes: Select alternative drug or reduce dose by 90%. Increase dose in response of hematologic monitoring efficacy |
|
| NUDT15 | rs116855232 | CC | CT, TT | ||
| Capecitabine, Fluorouracil# | CPIC/DPWG[6,20,21] Other variants are included in the DPWG guideline, but they are extremely rare[6] |
||||
| DPYD | rs3918290 | CC | CT, TT | CT: Reduce dose by 50%. TT: Change to alternative agents | |
| rs55886062 | AA | AC, CC | AC: Reduce dose by 50%. CC: Change to alternative agents | ||
| rs3918290+ rs55886062 | CC + AA | CT, TT + AC, CC | Change to alternative agents | ||
| rs67376798 | TT | AT, AA | Reduce dose by 50% | ||
| rs67376798+ rs3918290 | TT + CC | AT, AA + CT, TT | Change to alternative agents | ||
| rs67376798+ rs55886062 | TT + AA | AT, AA + AC, CC | Change to alternative agents | ||
| rs75017182 | GG | CG, CC | Reduce dose by 50%. | ||
| rs75017182+ rs3918290 | GG + CC | CG, CC + CT, TT | Change to alternative agents | ||
| rs75017182+ rs55886062 | GG + AA | CG, CC + AC, CC | Change to alternative agents | ||
| Tegafur | DPWG[6] | ||||
| DPYD | rs3918290 | CC | CT, TT | Homozygotes for any Risk genotype or combination of two heterozygotes: select alternative drug. Fluorouracil or capecitabine are not suitable alternatives because both are also metabolized by DPD. Other variants are included in the guideline, but they are extremely rare[6]. Tegafur has no longer recommendations from CPIC based on DPYD genotype. This is due to limited evidence regarding the impact of DPYD variants on tegafur toxicity risk | |
| rs72549303 | G/G | G/del, del/del | |||
| rs72549309 | ATGA/ATGA | ATGA/del, del/del | |||
| rs1801266 | GG | AG, AA | |||
| rs72549306 | CC | AC, AA | |||
| rs80081766+ rs78060119 | CC | CT, TT + AC, AA | |||
| rs55886062 | CC | AC, AA | |||
| rs1801265 | AA | AG, GG | |||
| rs1801268 | CC | AC, AA | |||
| Irinotecan | DPWG[6] | ||||
| UGT1A1 | rs8175347 | (TA)6/(TA)6 (TA)6/(TA)7 |
(TA)7/(TA)7 | Dose > 250 mg/m2: reduce initial dose by 30%. Increase dose in response to neutrophil count. Dose ≤ 250 mg/m2: no dose adjustment | |
| Ondansetron# | CPIC[21] | ||||
| CYP2D6 | - | PM, IM, NM | UM: *1/*1xN, *1/*2xN, *2/*2xN | Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron) | |
| Oxycodone | DPWG[6] | ||||
| CYP2D6 | NM | PM: two inactive alleles (*3-*8, *11-*16, *19-*21, *38, *40, *42); IM: two decreased-activity alleles (*9, *10, *17, *29, *36, *41) or carrying one active (*1, *2, *33, *35) and one inactive allele, or carrying one decreased-activity allele and one inactive allele | Select alternative drug (not tramadol or codeine) or be alert to insufficient efficacy | ||
| UM: gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles | Select alternative drug (not tramadol or codeine) or be alert to ADEs | ||||
| Tamoxifen | CPIC[22] More alleles exist, these are the most common[22] |
||||
| CYP2D6 | - | - | UM: *1/*1xN, *1/*2xN, *2/*2xN | Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day) | |
| - | - | NM: *1/*1, *1/*2, *1/*9, *1/*41, *2/*2 | Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day) | ||
| - | - | NM or IM (controversy remains): *1/*4, *1/*5, *41/*41; *4/*10, *4/*41, *5/*9; *10/*10, *10/*41 | Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day). Avoid CYP2D6 strong to weak inhibitors | ||
| - | - | PM: *3/*4, *4/*4, *5/*5, *5/*6 | Recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype and based on knowledge that CYP2D6 poor metabolizers switched from tamoxifen to anastrozole do not have an increased risk of recurrence. Note, higher dose tamoxifen (40 mg/day) increases but does not normalize endoxifen concentrations and can be considered if there are contraindications to aromatase inhibitor therapy | ||
| - | - | PM: see description in oxycodone | DPWG[6] Increased risk for relapse of breast cancer. Consider aromatase inhibitor for postmenopausal women |
||
| - | - | IM: see description in oxycodone | Increased risk for relapse of breast cancer. Avoid concomitant use of CYP2D6 inhibitors. Consider aromatase inhibitor for postmenopausal women | ||
| Tramadol | CYP2D6 | PM: see description in oxycodone | DPWG[6] Select alternative drug (not oxycodone or codeine) or be alert to insufficient effect |
||
| IM: see description in oxycodone | Be alert to decreased efficacy, consider dose increase. If still inadequate, do as PM | ||||
| UM: see description in oxycodone | Reduce dose by 30% and be alert to ADEs, or do as PM |
A summary of the published guidelines is shown in this table, translating the information to single SNPs when possible. The original guidelines, especially from CPIC, are much more extensive, so this table is only a comprehensive approach, useful for the majority of cases, but deeper details must be consulted in the original publications. #Applicable to pediatrics. Classical asterisks nomenclature: *1 is always considered the reference genotype. TPMT: *2 equivalent to rs1800462; *3A equivalent to *3B+*3C; *3B equivalent to rs1800460; *3C equivalent to rs1142345; *4 equivalent to rs1800584. NUDT15: *3 equivalent to rs116855232. UGT1A1: *28 equivalent to rs8175347 (this is not a real SNP, but a short tandem repeat polymorphism). DPYD at CPIC guideline: IM, one normal function + one no function, or one decreased function, or two decreased function alleles; PM, two no function, or one no function + one decreased function. No function: c.1905+1G>A equivalent to rs3918290 and DPYD*2A; c.1679 T>G equivalent to rs55886062 and DPYD*13; Decreased function: c.2846 A>T equivalent to rs67376798; c.1129-5923 C>G equivalent to rs75017182. CYP2D6: Date of access to CPIC-DPWG-PharmGKB for guidelines: 15 January 2019. ADE: Adverse Drug Event; UM: ultrarapid metabolizer; NM: normal metabolizer; IM: intermediate metabolizer; PM: poor metabolizer; CPIC: Clinical Pharmacogenetics Implementation Consortium; DPWG: Royal Dutch Association for the Advancement of Pharmacy - Pharmacogenetics Working Group; SNP: single nucleotide polymorphism