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Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

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Neha Chopra, Holly Tovey, Alex Pearson, Ros Cutts, Christy Toms, Paula Proszek, Michael Hubank, Mitch Dowsett, Andrew Dodson, Frances Daley, Divya Kriplani, Heidi Gevensleben, Helen Ruth Davies, Andrea Degasperi, Rebecca Roylance, Stephen Chan, Andrew Tutt, Anthony Skene, Abigail Evans, Judith M. Bliss & 2 more Serena Nik-Zainal, Nicholas C. Turner

Original languageEnglish
Article number2662
JournalNature Communications
Issue number1
Published1 Dec 2020

King's Authors


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.

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