| Abstract | Cilj: Anastrozol jelijek prvog izbora u liječenju poslijemenopauzalnih žena s hormonski ovisnim rakom dojke (HR-BC).Citokrom P450 (CYP) i UDP-glukuronoziltransferaza(UGT)imaju ključnu ulogu u deaktivaciji i uklanjanjuanastrozola. Negativanjeučinak anastrozola na koštani metabolizam dokazan, dok se učinak na Wnt inhibitore još uvijek istražuje. Cilj je istraživanja bio odrediti cirkulirajuće razine Wnt inhibitora u bolesnica s HR-BC liječenih anastrozolom i usporediti ih s bolesnicama oboljelima od raka dojke prije uvođenja terapije.Također smo ispitali povezanost Wnt inhibitora s mineralnom gustoćom kosti (BMD) te prehrambenim i životnim navikama. Polimorfizmijednog nukleotida (SNPs) u genima koji kodirajuCYP i UGTmogu imati ključnu ulogu u individualnim odgovorima na anastrozol. Cilj je bio utvrditi učestalost mutiranih CYP3A4*1B, CYP3A5*3 i UGT1A4*2 alela teistražiti njihovu povezanost s ishodom liječenjate pojavom nuspojava. Bolesnici i metode: U opažajno presječno istraživanje slučaja i kontrola je uključena 141 poslijemenopauzalna ispitanicas HR-BC,od kojih je 85 liječeno s 1 mg anastrozola, dok je 56 uključeno prije adjuvantne hormonske terapije. Serumske koncentracije Wnt inhibitora mjerene su pomoću komercijalno dostupnih ELISA testova. BMD; g/cm² izmjerena je denzitometrijom dvoenergetskim rendgenskim zrakama (eng. dual-energy X-ray absorptiometry, DXA) pomoću uređaja Lunar Prodigy (GE Healthcare, SAD), a upitnik je korišten za istraživanje osobitosti životnog stila i prehrambenih navikaispitanica. Genomska je DNA izolirana iz uzoraka periferne krvni upotrebom komercijalno dostupnog kompleta (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Njemačka). PCR u realnom vremenu upotrijebljen je za otkrivanje polimorfizama, uz primjenu specifičnog testa TaqMan® SNP genotipizacije (Applied Biosystems). Rezultati: Serumskesurazine sklerostina bile znatno više u skupini ispitanica liječenih anastrozolom (31,8 pmol/l) u usporedbi sa skupinom prije uvođenja hormonske terapije (24,1 pmol/l, p <0,001). Nasuprot tomu, razina DKK1 u serumu bilajeznatno niža u skupini liječenoj anastrozolom (24,3 pmol/l prema 26,02 pmol/l, p<0,001). BMD kuka i vrata bedrene kosti bio jeznatno niži u skupini liječenih anastrozolom. Statistički značajna negativna korelacija između sklerostina i DKK1 (rho=-0,287, p <0,001) zabilježena je u svih ispitanika. CYP3A5*3 predominantanjealel u hrvatskoj populaciji bolesnica s HR-BC. Dokazano je i istodobno postojanje heterozigotnog CYP3A4 *1B i CYP3A5*3 haplotipa u istoj skupini ispitanica.Zaključak: Povećanje serumske razine sklerostinai smanjenje razine DKK1 povezano je s liječenjemanastrozolom. Povezanost ispitivanihpolimorfizama s nastankom nuspojava liječenja nije dokazana. |
| Abstract (english) | Objectives: Anastrozole is the first choice treatmentinpostmenopausal women with hormone-dependent breast cancer (HR-BC). Cytokine P450 (CYP) and UDP-Glucuronosyltransferase (UGT) have a key role in deactivating and eliminating anastrozole. The negative effect of anastrozole on bone metabolism has been demonstrated, while the effect on Wnt inhibitors is still being investigated. The aim of the study was to determine the circulating levels of Wnt inhibitors in HR-BC patients treated with anastrozole and compare them with patients with breast cancer prior to theintroduction of the adjuvant hormonal therapy. We also investigated the association of Wnt inhibitors with bone mineral density (BMD) and dietary and life habits of participants. Single nucleotide polymorphisms (SNPs) in genes encoding CYP and UGT may play a key role in individual responses to anastrozole. The aim was to determine the frequency of mutated CYP3A4*1B, CYP3A5*3 and UGT1A4*2 alleles and to investigate their correlation with the outcome of adjuvant hormonal treatment and the occurrence of side effects. Participants and methods: Cross-sectional study included 141 postmenopausal HR-BC patients, of whom 85 were treated with 1 mg of anastrozole, and 56 were included prior to the introduction adjuvant hormonal therapy. Serum concentrations of Wntinhibitors were measured using commercially available ELISA assays. BMD; g/cm2 was measured by dual-energy x-ray absorptiometry (DXA) imaging (Lunar Prodigy, GE Healthcare, SAD) and a self-reported questionnaire was used to investigate the lifestyle and eating habits of the examinees. Genomic DNA was isolated from peripheral blood samples using commercially available kit (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Germany). A real-time PCR was used for the detection of polymorphisms, with the application of the specific TaqMan® SNP Genotyping Assay (Applied Biosystems). Results: Serum levels of sclerostin were significantly higher in the group of participants treated with anastrozole (31.8 pmol/l) compared to the w/o anastrozole therapy group (24.1 pmol/l,p<0.001). In contrast, the serum DKK1 level was significantly lower in the anastrozole treated group (24.3 pmol/l at 26.02 pmol/l, p <0.001). Total hip and femoral neckBMD were significantly lower in the group treated with anastrozole. Statistically significant negative correlation between sclerostin and DKK1 (rho=-0.287, p<0.001) was observed in all participants. CYP3A5*3 was found to be predominant in theCraotian population of HR-BC patients. We have demonstrateda strong linkage disequilibrium betweenCYP3A5*3 andCYP3A4*1B alleles in the same group of participants. Conclusion: Increased serum levels of sclerostin and decreased levels of DKK1 are associated with the anastrozole treatment. The correlation of the investigated polymorphisms with the onset of treatment side effects has not been established. |
