{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:30:01Z","timestamp":1787639401858,"version":"build-2736575974"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013831","name":"Universitatea de Medicin\u0103 \u015fi Farmacie din Craiova","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013831","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      CDK4\/6 inhibitors are standard-of-care for HR+\/HER2\u2212 advanced breast cancer, but grade 3\/4 neutropenia occurs in up to 60% of patients. Germline polymorphisms in\n                      <jats:italic>ABCB1<\/jats:italic>\n                      , encoding the P-glycoprotein efflux transporter, have been investigated as predictors of CDK4\/6 inhibitor\u2013induced neutropenia, with conflicting results across populations. No meta-analysis has previously pooled these findings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      PubMed, Scopus, and Web of Science were systematically searched. Studies reporting genotype-stratified grade 3\/4 neutropenia in CDK4\/6 inhibitor\u2013treated patients were eligible. Four SNPs were analyzed:\n                      <jats:italic>ABCB1<\/jats:italic>\n                      rs1128503,\n                      <jats:italic>ABCB1<\/jats:italic>\n                      rs1045642,\n                      <jats:italic>ERCC1<\/jats:italic>\n                      rs11615, and\n                      <jats:italic>ERCC1<\/jats:italic>\n                      rs3212986. Odds ratios were pooled using Mantel-Haenszel weighting with random-effects (rs1128503, rs11615) or fixed-effect (rs1045642, rs3212986) models under dominant genetic models, stratified by ancestry. The protocol was registered in PROSPERO (CRD420261379298).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four studies (1,138 patients) were included. No SNP showed a significant overall association. However, significant ancestry-dependent heterogeneity was detected for two\n                      <jats:italic>ABCB1<\/jats:italic>\n                      SNPs. For rs1045642, T-carrier status was significantly associated with increased neutropenia in European\/Caucasian patients (pooled OR 1.62, 95% CI 1.05\u20132.52, p = 0.03, I\n                      <jats:sup>2<\/jats:sup>\n                      = 0%) but decreased risk in East Asians (OR 0.31, 95% CI 0.13\u20130.74, p = 0.009; subgroup difference p = 0.0009). For rs1128503, a concordant European trend was observed (OR 1.87, 95% CI 0.87\u20134.00, p = 0.11) with reversed direction in North African\/Middle Eastern patients (OR 0.33, 95% CI 0.12\u20130.92, p = 0.03; subgroup difference p = 0.02). For\n                      <jats:italic>ERCC1<\/jats:italic>\n                      rs11615, the inclusion of Wang 2024 nullified the previously borderline European signal (pooled OR 0.99, 95% CI 0.42\u20132.33, p = 0.98, I\n                      <jats:sup>2<\/jats:sup>\n                      = 75%), with subgroup differences no longer significant (p = 0.17).\n                      <jats:italic>ERCC1<\/jats:italic>\n                      rs3212986 showed no association (OR 1.07, 95% CI 0.53\u20132.17, I\n                      <jats:sup>2<\/jats:sup>\n                      = 0%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These preliminary findings suggest that\n                      <jats:italic>ABCB1<\/jats:italic>\n                      rs1045642\u00a0T-carrier status may be associated with CDK4\/6 inhibitor\u2013induced neutropenia in European\/Caucasian patients, with a concordant trend for rs1128503 findings. Both associations appear ancestry-dependent, although the limited number of studies and single-study ancestry subgroups preclude definitive conclusions.\n                      <jats:italic>ERCC1<\/jats:italic>\n                      rs11615, previously borderline in a single study, was not confirmed upon independent replication. Prospective validation in adequately powered, ancestry-stratified cohorts incorporating\n                      <jats:italic>ABCB1<\/jats:italic>\n                      haplotype analysis and pharmacokinetic sampling is warranted.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>identifier CRD420261379298.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1872557","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:03:18Z","timestamp":1787637798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of germline ABCB1 and ERCC1 polymorphisms with CDK4\/6 inhibitor-induced neutropenia in patients with breast cancer: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Marina-Daniela","family":"Dimulescu","sequence":"first","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian Virgil","family":"Lungulescu","sequence":"additional","affiliation":[{"name":"Oncology Department, Faculty of Medicine, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca-Lelia","family":"Riza","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medicine, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Streata","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medicine, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radu Antoniu","family":"Patrascu","sequence":"additional","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca-Maria","family":"Capraru","sequence":"additional","affiliation":[{"name":"Doctoral School, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela-Simona","family":"Naidin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Management and Marketing, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan Silviu","family":"Ungureanu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana Andreea","family":"Gheonea","sequence":"additional","affiliation":[{"name":"Department of Radiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adina","family":"Turcu-Stiolica","sequence":"additional","affiliation":[{"name":"Department of Pharmacoeconomics, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova","place":["Craiova, Romania"]},{"name":"Department of Health Economics and Outcomes Research, Faculty of Medicine, University of Medicine and Pharmacy \u201cIuliu Hatieganu\u201d","place":["Craiova, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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