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

Autor: Bowen, Joanne, Braga, Sofia, Zotto, Valeria Dal, Finnie, John, DiPrimeo, Daniel, Cooke, Blaire, Bischof, Georg F., Wong, Alvin, Di Palma, Jack A.
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Zdroj: Physiological Reports; Aug2024, Vol. 12 Issue 16, p1-12, 12p
Abstrakt: The 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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