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dc.contributor.authorIwata, H
dc.contributor.authorUmeyama, Y
dc.contributor.authorLiu, Y
dc.contributor.authorZhang, Z
dc.contributor.authorSchnell, P
dc.contributor.authorMori, Y
dc.contributor.authorFletcher, O
dc.contributor.authorMarshall, J-C
dc.contributor.authorJohnson, JG
dc.contributor.authorWood, LS
dc.contributor.authorToi, M
dc.contributor.authorFinn, RS
dc.contributor.authorTurner, NC
dc.contributor.authorBartlett, CH
dc.contributor.authorCristofanilli, M
dc.date.accessioned2021-05-25T11:11:16Z
dc.date.available2021-05-25T11:11:16Z
dc.date.issued2021-05-05
dc.identifier.citationThe oncologist, 2021
dc.identifier.issn1083-7159
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4575
dc.identifier.eissn1549-490X
dc.identifier.eissn1549-490Xen_US
dc.identifier.doi10.1002/onco.13811
dc.identifier.doi10.1002/onco.13811en_US
dc.description.abstractBackground The most frequently reported treatment-related adverse event in clinical trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (ie, end of Week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia.Materials and methods ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib-treated patients from PALOMA-2 (n=584) and PALOMA-3 (n=442). SNP, race, and Cycle 1 Day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n=122) and non-Asian (n=530) ethnicity. Median progression-free survival (mPFS) was estimated using the Kaplan-Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed.Results ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non-Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR]=6.033, 95% CI=2.615-13.922, P<0.0001; Non-Asians: OR=6.884, 95% CI=4.138-11.451, P<0.0001). ABCB1_rs1128503 (C/C vs T/T: OR=0.57, 95% CI=0.311-1.047, P=0.070) and ERCC1_rs11615 (A/A vs G/G: OR=1.75, 95% CI=0.901-3.397, P=0.098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non-Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype.Conclusion This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135).Implications for practice Palbociclib plus endocrine therapy improves HR+/HER2- advanced breast cancer (ABC) outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy-induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (P<0.0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (P<0.10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.titleEvaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3.
dc.typeJournal Article
dcterms.dateAccepted2021-04-20
rioxxterms.versionAM
rioxxterms.versionofrecord10.1002/onco.13811
rioxxterms.licenseref.startdate2021-05-05
rioxxterms.licenseref.startdate2021-05-05en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe oncologist
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genetic Epidemiology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genetic Epidemiology
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamFunctional Genetic Epidemiology
icr.researchteamFunctional Genetic Epidemiologyen_US
dc.contributor.icrauthorFletcher, Oliviaen


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