Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.
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Authors
Chopra, N
Tovey, H
Pearson, A
Cutts, R
Toms, C
Proszek, P
Hubank, M
Dowsett, M
Dodson, A
Daley, F
Kriplani, D
Gevensleben, H
Davies, HR
Degasperi, A
Roylance, R
Chan, S
Tutt, A
Skene, A
Evans, A
Bliss, JM
Nik-Zainal, S
Turner, NC
Tovey, H
Pearson, A
Cutts, R
Toms, C
Proszek, P
Hubank, M
Dowsett, M
Dodson, A
Daley, F
Kriplani, D
Gevensleben, H
Davies, HR
Degasperi, A
Roylance, R
Chan, S
Tutt, A
Skene, A
Evans, A
Bliss, JM
Nik-Zainal, S
Turner, NC
Document Type
Journal Article
Date
2020-05-29
Date Accepted
2020-04-03
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.
Citation
Nature communications, 2020, 11 (1), pp. 2662 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Research Team
Molecular Oncology
Clinical Trials & Statistics Unit
Endocrinology
Translational Genomics
Clinical Trials & Statistics Unit
Endocrinology
Translational Genomics