Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.
Authors
Chopra, Neha
Tovey, Holly
Cutts, Ros
Toms, Christy
Proszek, Paula
Hubank, Michael
Dowsett, Mitch
Dodson, Andrew
Daley, Frances
Kriplani, Divya
Gevensleben, Heidi
Davies, Helen
Roylance, Rebecca
Chan, Stephen
Tutt, Andrew
Skene, Anthony
Evans, Abigail
Bliss, Judith M
Turner, Nicholas C
Publication Date
2020-05-29Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
11
Issue
1
Pages
2662
Language
eng
Type
Article
This Version
AM
Physical Medium
Electronic
Metadata
Show full item recordCitation
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.. Nat Commun, 11 (1), 2662. https://doi.org/10.1038/s41467-020-16142-7
Abstract
Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, 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 end point, decreased Ki67, occured in 12% of TNBC. In secondary end point 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.
Keywords
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
Sponsorship
Cancer Research UK (23916)
Cancer Research UK (23433)
Cancer Research UK (25274)
Identifiers
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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