Preclinical and clinical evaluation through serial colonoscopic evaluation of neratinib-induced diarrhea in HER2-positive breast cancer-A pilot study.

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dc.contributor.authorBowen, J.
dc.contributor.authorBraga, S.
dc.contributor.authorZotto, V.D.
dc.contributor.authorFinnie, J.
dc.contributor.authorDiPrimeo, D.
dc.contributor.authorCooke, B.
dc.contributor.authorBischof, G.F.
dc.contributor.authorWong, A.
dc.contributor.authorDi Palma, J.A.
dc.date.issued2024
dc.description.abstractThe irreversible pan-HER tyrosine kinase inhibitor neratinib is approved for patients with HER2-positive, early-stage and metastatic breast cancer (BC). Neratinib-associated diarrhea is the most common reason for early discontinuation. Preclinical studies identified mechanisms of neratinib-induced diarrhea and rationale for prophylactic and preventive measures. We studied effects of neratinib on rat intestines and conducted a phase 2 study of colon pathogenesis in patients with HER2-positive BC treated with neratinib (NCT04366713). Colon samples from female albino Wistar rats receiving neratinib or vehicle were examined for histopathological changes. Patients with HER2-positive BC received neratinib 240 mg once daily for up to 1 year. Colonoscopy biopsies were collected at baseline and at Day 28 to identify changes consistent with rat pathologies. Rat colons were markedly altered in appearance, with similar short circuit currents (Isc) and responses to carbachol and forskolin. Mucosal barrier loss and/or significant increase in secretory propensity in neratinib-versus control-treated animals were not seen. Two of four endpoint-evaluable patients presented with mild pathological changes, largely comparable with the rat model. Preclinical evidence supports an inflammatory component of neratinib-induced diarrhea without mucosal barrier function loss. Colonoscopy findings in patients with BC indicate mild or no pathological changes in the colon due to neratinib treatment.
dc.description.statementofresponsibilityJoanne Bowen, Sofia Braga, Valeria Dal Zotto, John Finnie, Daniel DiPrimeo, Blaire Cooke, Georg F. Bischof, Alvin Wong, Jack A. Di Palma
dc.identifier.citationPhysiological Reports, 2024; 12(16):e70008-1-e70008-12
dc.identifier.doi10.14814/phy2.70008
dc.identifier.issn2051-817X
dc.identifier.issn2051-817X
dc.identifier.orcidBowen, J. [0000-0003-0876-0031]
dc.identifier.orcidFinnie, J. [0000-0003-2277-1693]
dc.identifier.urihttps://hdl.handle.net/2440/144901
dc.language.isoen
dc.publisherWiley
dc.rights© 2024 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.14814/phy2.70008
dc.subjectAged
dc.subjectAnimals
dc.subjectAntineoplastic Agents
dc.subjectBreast Neoplasms
dc.subjectColon
dc.subjectColonoscopy
dc.subjectDiarrhea
dc.subjectFemale
dc.subjectHumans
dc.subjectMiddle Aged
dc.subjectPilot Projects
dc.subjectQuinolines
dc.subjectRats
dc.subjectRats, Wistar
dc.subjectReceptor, ErbB-2
dc.subjectcolonoscopy study
dc.subjectHER2‐positive breast cancer
dc.subjectneratinib
dc.subjectrat model
dc.subjectcolonoscopy study; diarrhea; HER2-positive breast cancer neratinib; rat model
dc.subject.meshColon
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshRats
dc.subject.meshRats, Wistar
dc.subject.meshBreast Neoplasms
dc.subject.meshDiarrhea
dc.subject.meshQuinolines
dc.subject.meshReceptor, erbB-2
dc.subject.meshAntineoplastic Agents
dc.subject.meshColonoscopy
dc.subject.meshPilot Projects
dc.subject.meshAged
dc.subject.meshMiddle Aged
dc.subject.meshFemale
dc.titlePreclinical and clinical evaluation through serial colonoscopic evaluation of neratinib-induced diarrhea in HER2-positive breast cancer-A pilot study.
dc.typeJournal article
pubs.publication-statusPublished

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