{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:49:53Z","timestamp":1791528593562,"version":"4.3.4"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Hepatotoxicity is an increasingly recognised and potentially dose\u2010limiting adverse effect of CDK4\/6 inhibitors, but their histopathological spectrum remains incompletely characterised. We aimed to describe the clinicopathological features of histologically characterised CDK4\/6 inhibitor\u2010induced liver injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      We retrospectively identified patients with metastatic breast cancer who developed liver enzyme elevation and underwent liver biopsy while receiving a CDK4\/6 inhibitor at a single comprehensive cancer centre (2020\u20132024). Inclusion required a RUCAM score \u22656 and exclusion of alternative aetiologies. Seven female patients met the criteria (ribociclib,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096; palbociclib,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20091). The mean interval to first enzyme elevation was 60\u2009days (range 20\u2013114) and the mean RUCAM score was 8. Antinuclear antibody (ANA) positivity was noted in three patients, with negative extended autoimmune panels. Liver biopsy demonstrated severe acute hepatitis in five patients (71.4%), mild lobular hepatitis in one (14.3%) and subacute hepatitis with early fibrosis in one (14.3%). All acute biopsies showed perivenular (zone 3) confluent necrosis, with additional bridging necrosis in three biopsies. Portal inflammation was identified in all biopsies and lymphocytic cholangitis in five (71.4%) biopsies. No ANA\u2010positive patient showed histological features of autoimmune hepatitis. All patients achieved biochemical normalisation after drug withdrawal (mean 63\u2009days from peak; range 30\u2013129), and six were successfully switched to an alternative agent.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CDK4\/6 inhibitor\u2010induced liver injury predominantly manifests as acute hepatocellular injury with zone 3 necrosis and lymphocytic cholangitis. Despite severe histological abnormalities, it resolves with drug withdrawal, and limited cross\u2010reactivity between agents supports individualised therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/his.70294","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:00:19Z","timestamp":1791525619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclin\u2010dependent kinase 4\/6 (\n                    <scp>CDK4<\/scp>\n                    \/6) inhibitor\u2010induced hepatotoxicity and its resolution: a study of seven cases"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5091-4992","authenticated-orcid":false,"given":"Sunayana","family":"Misra","sequence":"first","affiliation":[{"name":"Department of Pathology Sir Ganga Ram Hospital  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0413-034X","authenticated-orcid":false,"given":"Lisa","family":"Centeno","sequence":"additional","affiliation":[{"name":"Department of Pathology City of Hope National Medical Center  Duarte CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9376-8258","authenticated-orcid":false,"given":"Dupinder","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Hepatology City of Hope National Medical Center  Duarte CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1872-0431","authenticated-orcid":false,"given":"Romil","family":"Saxena","sequence":"additional","affiliation":[{"name":"Department of Pathology Emory University School of Medicine  Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1735-7770","authenticated-orcid":false,"given":"Rifat","family":"Mannan","sequence":"additional","affiliation":[{"name":"Department of Pathology City of Hope National Medical Center  Duarte CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1056\/NEJMoa1609709","article-title":"Ribociclib as first\u2010line therapy for HR\u2010positive, advanced breast cancer","volume":"375","author":"Hortobagyi GN","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21061960","article-title":"The roles of cyclin\u2010dependent kinases in cell\u2010cycle progression and therapeutic strategies in human breast cancer","volume":"21","author":"Ding L","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1080\/14740338.2025.2468357","article-title":"Hepatic adverse events with CDK4\/6 inhibitors: a systematic review combining meta\u2010analysis and FAERS database","volume":"25","author":"Tang Y","year":"2026","journal-title":"Expert Opin. Drug Saf."},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhepr.2024.101098","article-title":"CDK4\/6 inhibitor\u2010induced liver injury: clinical phenotypes and role of corticosteroid treatment","volume":"6","author":"Meunier L","year":"2024","journal-title":"JHEP Rep."},{"key":"e_1_2_10_6_1","article-title":"Hepatotoxicity across CDK 4\/6 inhibitors: a narrative review","volume":"33","author":"Wong WHF","year":"2025","journal-title":"Support Care Cancer"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejca.2025.115225","article-title":"Efficacy, safety, and patient\u2010reported outcomes across young to older age groups of patients with HR+\/HER2\u2010 advanced breast cancer treated with ribociclib plus endocrine therapy in the randomized MONALEESA\u20102, \u20103, and \u20107 trials","volume":"217","author":"Hart LL","year":"2025","journal-title":"Eur. J. Cancer"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ejca.2018.05.017","article-title":"Palbociclib plus endocrine therapy in older women with HR+\/HER2\u2010 advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies","volume":"101","author":"Rugo HS","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.annonc.2024.08.1969","article-title":"Real\u2010world evidence of ribociclib induced liver toxicity in patients with breast cancer: a multi\u2010center experience","volume":"35","author":"Bas O","year":"2024","journal-title":"Ann. Oncol."},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1080\/0284186X.2020.1853228","article-title":"Hepatotoxicity associated with ribociclib among breast cancer patients","volume":"60","author":"Finnsdottir S","year":"2021","journal-title":"Acta Oncol."},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1177\/10781552211027931","article-title":"A case report of fulminant hepatitis due to ribociclib with confirmed by liver biopsy in breast cancer","volume":"28","author":"Topcu A","year":"2022","journal-title":"J. Oncol. Pharm. 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An international transporter consortium perspective","volume":"104","author":"Kenna JG","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S1470-2045(15)00613-0","article-title":"Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone\u2010receptor\u2010positive, HER2\u2010negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA\u20103): final analysis of the multicentre, double\u2010blind, phase 3 randomised controlled trial","volume":"17","author":"Cristofanilli M","year":"2016","journal-title":"Lancet Oncol."},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3138\/canlivj-2021-0015","article-title":"Palbociclib\u2010induced severe hepatitis: a case study and literature review","volume":"4","author":"Hyppolite JJ","year":"2021","journal-title":"Can. Liver J."},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.17161\/kjm.v13i1.13628","article-title":"Palbociclib\u2010induced liver failure","volume":"13","author":"Atallah R","year":"2020","journal-title":"Kans. J. Med."},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1002\/hep.28720","article-title":"Pseudocirrhosis and liver failure in patients with metastatic breast cancer after treatment with palbociclib","volume":"65","author":"Vuppalanchi R","year":"2017","journal-title":"Hepatology"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2023.1256783","article-title":"Ribociclib\u2010induced liver injury: A case report","volume":"13","author":"Schaeffer S","year":"2023","journal-title":"Front. 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Chemother."},{"key":"e_1_2_10_27_1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/his.14000","article-title":"Immune\u2010related adverse reactions in the hepatobiliary system: second\u2010generation check\u2010point inhibitors highlight diverse histological changes","volume":"76","author":"Zen Y","year":"2020","journal-title":"Histopathology"},{"key":"e_1_2_10_28_1","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41379-020-00653-1","article-title":"Liver biopsy findings in patients on immune checkpoint inhibitors","volume":"34","author":"Cohen JV","year":"2021","journal-title":"Mod. Pathol."},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.jhep.2018.01.033","article-title":"Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors","volume":"68","author":"De Martin E","year":"2018","journal-title":"J. Hepatol."},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1053\/j.semdp.2019.07.009","article-title":"Checkpoint inhibitor\u2010induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy","volume":"36","author":"Zen Y","year":"2019","journal-title":"Semin. Diagn. Pathol."},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"696","DOI":"10.3390\/medicina59040696","article-title":"Does the rechallenge with another CDK 4\/6 inhibitor in breast cancer work? A case report and literature review","volume":"59","author":"Stanciu IM","year":"2023","journal-title":"Medicina (Kaunas)"},{"key":"e_1_2_10_32_1","article-title":"Hepatotoxicity after CDK 4\/6 inhibitor initiation in the treatment of hormone\u2010positive metastatic breast cancer","volume":"15","author":"Wani K","year":"2023","journal-title":"Cureus"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70294","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/his.70294","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70294","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:00:23Z","timestamp":1791525623000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.70294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":31,"alternative-id":["10.1111\/his.70294"],"URL":"https:\/\/doi.org\/10.1111\/his.70294","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"2026-04-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"his.70294"}}