Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.
Nik-Zainal Abidin, Serena
Turner, Nicholas C
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Chopra, N., Tovey, H., Pearson, A., Cutts, R., Toms, C., Proszek, P., Hubank, M., et al. (2020). Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.. Nature communications, 11 (1), 2662. https://doi.org/10.1038/s41467-020-16142-7
Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary endpoint, decreased Ki67, occured in 12% of TNBC. In seconday endpoint analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.
Humans, Indoles, BRCA1 Protein, BRCA2 Protein, Adult, Aged, Middle Aged, Female, Rad51 Recombinase, Recombinational DNA Repair, Triple Negative Breast Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Whole Genome Sequencing, Circulating Tumor DNA
Cancer Research UK (23916)
Cancer Research UK (23433)
Cancer Research UK (25274)
External DOI: https://doi.org/10.1038/s41467-020-16142-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/304149
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