Molecular mechanisms of PARP inhibitor sensitivity in primary triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harbouring evidence of defective homologous recombination (HR) DNA repair. At present there are no biomarkers available in the clinic to identify this subgroup and hence the mainstay of treatment remains to be chemotherapy. The objectives of the work presented here were to: - Identify biomarkers of homologous recombination deficiency in TNBC - Assess the response activity of PARP inhibition in primary sporadic TNBC Initial validation work used samples from the ChemoNEAR study to optimise a functional biomarker of HR deficiency using RAD51 immunohistochemistry (IHC). Using next generation sequencing techniques, a BRCA1 and RAD51C methylation multiplex was designed using bisulfite sequencing in breast cancer samples from the ChemoNEAR study. Taking these two techniques forward into the RIO trial (EudraCT 2014-003319-12), a phase 2 window clinical trial, along with HRDetect, a mutational-signature based classifier, a subgroup of HR deficient TNBC was identified. Whether this subgroup of TNBC, representing the phenotype BRCAness can demonstrate activity to PARP inhibition, was assessed using tissue and liquid derived biomarkers, Ki67 and circulating tumour DNA (ctDNA) respectively. Although Ki67 was not an effective biomarker of response activity, ctDNA dynamics were able to demonstrate response to activity with PARP inhibition in germline BRCA and HR deficient TNBC patients. The identification of HR deficient TNBC is of vital clinical importance if treatment for this aggressive breast cancer subtype is to improve. The work presented here shows that a subgroup of HR deficient TNBC can be identified using functional and genomic biomarkers. PARP inhibition is a promising treatment in this cohort of patients and using ctDNA dynamics, changes in response to treatment can be assessed. This needs further validation in larger clinical trials to ascertain the most useful biomarker for HRD prediction to guide treatment decisions.