Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.
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Date
2020-05-29ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
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
Research team
Molecular Oncology
Clinical Trials & Statistics Unit
Endocrinology
Translational Genomics
Language
eng
Date accepted
2020-04-03
License start date
2020-05-29
Citation
Nature communications, 2020, 11 (1), pp. 2662 - ?
Publisher
NATURE PORTFOLIO