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:
|
Authors | Hiroji Iwata, Yoshiko Umeyama, Yuan Liu, Zhe Zhang, Patrick Schnell, Yuko Mori, Olivia Fletcher, Jean-Claude Marshall, Jillian G Johnson, Linda S Wood, Masakazu Toi, Richard S Finn, Nicholas C Turner, Cynthia Huang Bartlett, Massimo Cristofanilli |
Journal | The oncologist
(Oncologist)
Vol. 26
Issue 7
Pg. e1143-e1155
(07 2021)
ISSN: 1549-490X [Electronic] England |
PMID | 33955129
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. |
Chemical References |
- Piperazines
- Pyridines
- Receptor, ErbB-2
- palbociclib
|
Topics |
- Antineoplastic Combined Chemotherapy Protocols
- Breast Neoplasms
(drug therapy)
- Female
- Humans
- Neutropenia
(chemically induced, genetics)
- Pharmacogenomic Testing
- Piperazines
- Pyridines
- Receptor, ErbB-2
(therapeutic use)
|