Page 86 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
grade ≥ 3
haematological
toxicity
grade ≥ 3
grade ≥ 3 gastrointestinal
hgraaedmea≥to3logical toxicity
t h f l o a u x e o i mc r o i t a p y t y o r l i o m g i i d c a i n l e -
gtoraxidceity≥ 3 induced death
x 0.26 (S) 66%
x 0.20 (S) 56% x 0.26 (S) 66% x 0.26 (S) 66% NS 10% x 0.20 (S) 56% x 0.20 (S) 56%
ref. 9 – FU/CAP, mono/comb Meulendijks
ref. 9 – D et al.
Fr eUf /. C9 A–P , Clinical
mFUo/nCoA/Pc,omb relevance of
MmDPoeYnuDole/vncadorimijaknbsts
DMetulaeln. dijks c.1679T>G,
CDlienticaal.l c.1236G>A/H
rCaeplilnBei3vca,anal nced of
DrePleYvDavnacreiaonfts c.1601G>A as
cD.P1Y6D79vTa>rGia,nts predictors of
cse.1v26e37re69GT>GA,/H
ac.p1B23,6aGn>dA/H fluoropyrimidi
ca.p1B630,1aGn>dA as ne-associated
pc.r1e6d0ic1tGo>rsAoafs sperevedricetors of fsleuvoerroepyrimidi fnleu-oarsospoycriaimteidi ne-associated
Level of evidence score: 4
Level of gene act.
eL ev vi de el no cf e 1: CTC-
secvoidre:n4ce AE 4
score: 4
gene act. gene act.
1ge: nCeTCa-ct. 1-1.5:
1AC:TEC4T-ACE- 4 AE 4 gene act. 1ge-1n.e5:act. 1C -T1C. -5A: E 4 CTC-AE 4
9.9
Authors’ conclusion: ‘DPYD variants c.1679T>G and c.1236G>A/HapB3
Authors’ conclusion: are clinically relevant
‘ADuPtYhDorvsa’ rcioanctslusion: predictors of
‘cD.1P6Y7D9Tva>rGiaanntds fluoropyrimidine-
ca.s1s26o37c69iaGTt>e>GdA/taHonxadipcBit3y.
ac.r1e2c3l6inGic>aAll/yHraepleBv3ant Upfront screening for
paredcilcintoicraslloyfrelevant these variants, in
fpaldruedodirtioicoptnoyrtsiomotifhdeine-
aflsusorcoiaptyerdimtiodxiniceit-y. established variants
Uaspsforcoinatesdcrteoexnicinitgy.for DPYD*2A and
tUch.p2ef8sr4eo6nvAta>rsiTcar,neistesn, ing for
athdedsietiovnartioantthse, in recommended to
ea ds t d a i bt i l o i s n h et o d t v h a e r i a n t s improve the safety of
DesPtYaDbl*is2hAeadnvdariants cD.P2Y8D46*A2A>Ta,nisd
r c e . 2 c 8 o 4 m 6 mA > e T n , d i e s d t o irmecpormovmeetnhdeesdafteoty of
garasdtreo≥in3testinal
tgPoaexsritcreiotnyintatgeestoinfaplatients with toxicity for *1/*2A on
ftlouxoicroitpyyrimidine- NS
reduced dosing compared to *1/*1 on full dosing:
10% ifnludourcoepdyrdiemaitdhine- NS 10%
induced death
Percentage of patients with toxicity for *1/*2A on
any toxicity grade ≥ NS
*1/*1
rPedrcuecnetdadgeosoinf gpactoimenptasrwedithtoto*x1i/c*it1y ofonrf*u1ll/d*o2sAinogn: 3
reduced dosing compared to *1/*1 on fuvlladluoesifnogr:
haematolog
any toxicity ical toxicity
any toxicity diarrhoea
haematolog hand-foot
i h c a a e l mt o a x t i c o i l t o y g syndrome
grade 1-2 NS 54%
*va1l/u*e1for grade ≥ 3 NS 10%
grade ≥ NS 2*13/%*1 grade 1-2 NS 35%
3grade ≥ NS 23% grade ≥ 3 NS 8%
g3grade 1-2 NS 5249%
grade ≥1-32 NS 1504% grade ≥ 3 NS 5%
grade 1≥-32 NS 3150% grade 1-2 NS 28%
diTchiaelrrtaohuxotiehcaiotyrs indgicratdeeth≥1-a32t theNcSomparable83%5to%xicity
dbiuarrdrehnoesauggestsgrtahdaet *1≥1-32/*2ANisSnot under28e9%x%posed
h a n d - f o o t g g r r a a d d e e ≥1 - 32 N N S S 52 %9 % when treated with a median dose of 48%.
shyandr-ofomoet grade 1≥-32 NS 258%%
Tsyhnedaruotmheors indgicratdeeth1-a2t theNcSomparable28to%xicity Dose-normalised pharmacokinetics and DPD
bThuerdaeunthsuogrsgeinsdtsictahtaett*h1a/t*t2hAe icsonmopt aurnadbeleretxopxoicsietyd enzyme activity for *1/*2A compared to *1/*1:
wbuhrednentresuagtegdeswtsitthatm*e1d/*ia2nAdisosneotouf n48d%er.exposed value
when treated with a median dose of 48%. for Dose-normalised pharmacokinetics and DPD*1/*1
Denozsyem-neoramctaivlisteydfoprh*a1r/m*a2cAockoinmeptiacsreadntdoD*P1D/*1: 5-FU AUC normalised to a x 2.03 602
ceanpzyemciteabacintievidtyosfeoro*f1/2*520A com(NpaS)red to *n1g/v.*ha1/l:umel
for value
*fo1r/*1 9.9
6n0m*2o1l/*h1r
n60g.2h/ml per mg
ng.h/ml protein
pDePrDipehnezryaml meoanctoinviutycleinar (xS0).64 n9.m9ol/ hr patients treated with 5-FU or capecitabine, either as
mg/m
DPD enzyme activity in 5p-eFrUiphAeUrCalnmoromnoalnisuecdletaor a
c5a-FpUecAitUaCbinoerdmoasleisoefd1t2o5a0 blood cells
2
mcagp/emcitabine dose of 1250
2
DmPgD/menzyme activity in
2
x 0.64 Meta-analysis of 8 cohort studies with in total 7365
bpleoroipdhceerlalsl mononuclear (S) pnemroml/ghr combined chemotherapy (different combinations) or
blood cells preortmeign as monotherapy (with or without radiotherapy).
Meta-analysis of 8 cohort studies with in totparlo7t3e6in5 Data on *13 were derived from 5 studies including a
x 0.64 x(S2) .03 (xN2S.)03 (NS)
value for
23%
pMaetitean-atsnatrlyesaitseodf w8 icthoh5o-FrtUsoturdciaepsewcitahbininteo, teailth7e3r6a5s total of 5,616 patients and 11 carriers of *13. Data on
pcoamtiebnintsedtrechateemdowthitehra5p-FyU(doirffcearepnetcictoabminbein, aetiitohnesr)aosr c.1236G>A were derived from 6 studies including a
tcaostmalboinfoe4td,h2ce6hr1aepmyaot(itwehniettrhsaoapnrydw(d1iti7fhf4oeruhetenrttaecdroiozmtyhbgeoinruaspticyoa)n.rsri)eorrs
aDsatmaono*th1e3rwapeyre(wdiethrivoerdwfirtohmou5t srtauddioieths einraclpuyd)i.ng a and 3 homozygous carriers of c.1236A>G. Data on
Dtoattal ofn5*,16316wpearteiednetrsivaendf1ro1mca5rrsietursdioefs*in1c3l.uDdaintag aon *2A were derived from 7 studies including a total of
5tco.17t2a3l37o6pfGa5>t,Ai6e1nw6tespraeantdiden6rti0vsecadnrfdrrieo1rm1s co6afrs*rtiu2eAdrsi.eDosfaint*ac1l3ou.ndDinagtaon
cto.1t2al3o6fG4>,A26w1epreatdienrtivseadnfdro1m746hsettuedroiezsyignoculusdcianrgriaers c.2846A>T were derived from all 8 studies including a
t a o n t d a l 3 o h f o 4 m, 2 o 6 z 1 y p g o a t u i s e n c a t s r r a i e n r d s 1 o 7 f 4 c . h 1 e 2 t 3 e 6 r A o z > y G g . o D u a s t c a a o r r n i e r s total of 7,318 patients and 85 carriers of c.2846A>T.
1a*n2odAf 3twhheore8mdsoteuzrydivgieosduisfnrcotahmrirsi7emrssetuotadf-icae.ns1a2inl3yc6sluiAsd>iisGna.glDsaoatoiantcoallnuodfed
*52.7A37wperaetiednetrsivaenddfr6o0mca7rrsiteurdsioesf *in2cAlu. dDiantgaaotnotal of in the meta-analysis of Rosmarin 2014 (Rosmarin
5c.2783476pAa>tTiewntesraendder6i0vecdarfrioemrs aolfl *82sAtu. dDiaetsainocnluding a 2014). 2 of the 8 studies in this meta-analysis are also
cto.2t8al4o6fA7>,T31w8epreatdienritvseadnfdro8m5 caallr8riesrtsudoifecs.2in8c4lu6dAi>nTg. a t1ootaflthoef 78,3s1tu8dpieastiiennthsiasnmde8t5a-caanrarliyesrissoisf ca.l2so84in6cAlu>Td.ed 1inotfhtehme e8tsat-uadniaelsysinistohfisRmosemta-raina2l0ys1i4s i(sRaolsmoainricnluded i2n0t1h4e).m2eotfat-hanea8lysstiusdoifesRoinsmthaisrimn 2e0ta1-4an(Raolysmisarrien also 2014). 2 of the 8 studies in this meta-analysis are also
improve the safety of
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