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.
Highlights
Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair
Treatment naïve TNBC were treated with the PARP inhibitor rucaparib for 2 weeks prior to surgery or neoadjuvant chemotherapy
In pre-planned secondary analyses, we show that cancers with HR deficiency can be robustly identified with the mutational-signatures based classifier HRDetect (Fig. 2 and Supplementary Fig. 1), which identifies cancers with a functional deficiency in HR (Fig. 3b), and with evidence of activity of PARP inhibitors restricted to these cancers using Circulating tumour DNA (ctDNA) analysis (Fig. 3c)
Summary
Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors. Advances in whole-genome sequencing (WGS) have lead to the identification of mutational processes that leave a characteristic imprint, a mutational signature on the cancer genome. These have revolutionalised our understanding of cancer and has the capability to improve diagnosis and treatment of cancer[5,6].
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