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

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.

Determining homologous recombination deficiency scores with whole exome sequencing and their association with responses to neoadjuvant chemotherapy in breast cancer

“…We found that a majority ( n = 8) of 12 patients with gHRRm had HRD-high tumors consistent with previous reports [ 4 , 7 , 8 , 10 , 11 , 21 , [32] , [33] , [34] , [35] , [36] ]. These eight patients had BRCA1 or BRCA2 germline mutations.…”

Olaparib monotherapy as primary treatment in unselected triple negative breast cancer

“…Notably, different genomic signatures for HRD or BRCAness have been tested as potential predictive markers for platinum or PARP inhibitor sensitivity, revealing conflicting results. 12,26,36,42 Here, 69% of TNBC harbored a basal-like subtype by PAM50 analysis, but the basal-like subtype was not enriched among olaparib responders. Also, using MLPA analysis, we found the BRCA1-like signature not to be predictive of response to olaparib in the current patient cohort.…”

Pan-cancer landscape of homologous recombination deficiency

“…Our results thus indicate that a large number of patients who would potentially benefit from PARPi therapy still remain unnoticed. Since the mutational phenotype of HRD is independent of cancer type, mutational scar based HRD detection such as with CHORD would be valuable for cancer type agnostic patient stratification for future PARPi trials 31 . This is particularly important for metastatic patients (who depend on systemic treatments and benefit most from targeted treatments like PARPi), as well as for cancer types currently lacking good markers for patient stratification for such treatment (such as prostate 32 and biliary 33 cancer).…”