Abstract Introduction: Micronucleated reticulocytes (MN-RET) are a well-established biomarker of chromosomal damage, and their assessment is traditionally included as part of regulatory-based, product safety testing during preclinical development. Adaptation of the methodology to high-throughput flow cytometric analysis broadened the utility of the assay and enabled practical translation to human subjects. Most recently, this methodology has been used to demonstrate target engagement via the induction of MN-RET as a biomarker of efficacy during the development of therapies targeting DNA double strand break-repair pathways. Methods: To support this application, we have conducted studies in clinical models to define basic methodological parameters. In an effort to better understand baseline values over time/between subjects and reproducibility, we evaluated technical replicate variability in MN-RET frequencies based on blood specimens from 14 subjects. Intra-subject variability was based on serial blood draws from 6 subjects, and inter-subject variation was based on up to 344 subjects age 0 to 73 years. Results Human models demonstrate increased MN-RET frequencies following exposure to known DNA damaging agents. Inter-subject variation (≥77%) was much greater than intra-subject and technical replicate variability. The relatively large inter-subject variation is apparent from mean and standard deviation values for MN-RET (0.15 ± 0.10%). Neither age nor sex affected inter-subject variation of the MN-RET frequency. In a clinical setting, patients treated with PARP inhibitors at a labelled dose showed elevated MN-RETs, demonstrating the increased unrepaired DNA damage as an indicator of target engagement induced by treatment. Summary: This translational biomarker of chromosomal damage represents a unique and powerful tool for use in the development of cancer therapies that elicit DNA double strand breaks. Citation Format: Jeffrey C. Bemis, Colette Baxter, Gillian Langford, Timothy A. Yap, Susanna Varkey Ulahannan, Nehal Lakhani, Babar Bashir, Kathleen N. Moore, Payal Shah, Svetlana Avlasevich, Dorothea Torous, Stephen Dertinger. Human blood micronucleated reticulocytes: Application as a pharmacodynamic biomarker for DNA double strand breaks in oncology drug development abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3148.
Bemis et al. (Fri,) studied this question.
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