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Preclinical and clinical evaluation through serial colonoscopic evaluation of neratinib-induced diarrhea in HER2-positive breast cancer-A pilot study.
Bowen, Joanne; Braga, Sofia; Zotto, Valeria Dal; Finnie, John; DiPrimeo, Daniel; Cooke, Blaire; Bischof, Georg F; Wong, Alvin; Di Palma, Jack A.
Afiliación
  • Bowen J; School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia.
  • Braga S; Medical Oncology, Hospital Prof. Doutor Fernando Fonseca, EPE, Amadora, Portugal.
  • Zotto VD; Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Finnie J; Division of Research and Innovation, University of Adelaide, Adelaide, South Australia, Australia.
  • DiPrimeo D; Puma Biotechnology, Inc., Los Angeles, California, USA.
  • Cooke B; Puma Biotechnology, Inc., Los Angeles, California, USA.
  • Bischof GF; Puma Biotechnology, Inc., Los Angeles, California, USA.
  • Wong A; Puma Biotechnology, Inc., Los Angeles, California, USA.
  • Di Palma JA; Division of Gastroenterology, University of South Alabama, College of Medicine, Mobile, Alabama, USA.
Physiol Rep ; 12(16): e70008, 2024 Aug.
Article en En | MEDLINE | ID: mdl-39187401
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinolinas / Neoplasias de la Mama / Colonoscopía / Ratas Wistar / Receptor ErbB-2 / Diarrea Límite: Aged / Animals / Female / Humans / Middle aged Idioma: En Revista: Physiol Rep Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinolinas / Neoplasias de la Mama / Colonoscopía / Ratas Wistar / Receptor ErbB-2 / Diarrea Límite: Aged / Animals / Female / Humans / Middle aged Idioma: En Revista: Physiol Rep Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos