dc.contributor.author | Iwata, H | |
dc.contributor.author | Umeyama, Y | |
dc.contributor.author | Liu, Y | |
dc.contributor.author | Zhang, Z | |
dc.contributor.author | Schnell, P | |
dc.contributor.author | Mori, Y | |
dc.contributor.author | Fletcher, O | |
dc.contributor.author | Marshall, J-C | |
dc.contributor.author | Johnson, JG | |
dc.contributor.author | Wood, LS | |
dc.contributor.author | Toi, M | |
dc.contributor.author | Finn, RS | |
dc.contributor.author | Turner, NC | |
dc.contributor.author | Bartlett, CH | |
dc.contributor.author | Cristofanilli, M | |
dc.date.accessioned | 2021-05-25T11:11:16Z | |
dc.date.available | 2021-05-25T11:11:16Z | |
dc.date.issued | 2021-06-07 | |
dc.identifier.citation | The oncologist, 2021 | |
dc.identifier.issn | 1083-7159 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4575 | |
dc.identifier.eissn | 1549-490X | |
dc.identifier.doi | 10.1002/onco.13811 | |
dc.description.abstract | BACKGROUND: 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 (i.e., 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% confidence interval [CI], 2.615-13.922, p < .0001; Non-Asians: OR, 6.884, 95% CI, 4.138-11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311-1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901-3.397, p = .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 hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer 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 < .0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (p < .10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.title | Evaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-04-20 | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1002/onco.13811 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2021-05-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The oncologist | |
pubs.notes | Not 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-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Functional Genetic Epidemiology | |
icr.researchteam | Functional Genetic Epidemiology | |
dc.contributor.icrauthor | Fletcher, Olivia | |
dc.contributor.icrauthor | Turner, Nicholas | |