Better understanding the role of PARP inhibitors in triple-negative breast cancer

Saima Hassan

Breast cancer is the most common cancer in women. Triple-negative breast cancers (TNBCs) lack expression of hormone receptors and HER2, have an earlier onset of recurrent disease, and a shorter overall survival. Potent PARP inhibitors (PARPi) such as talazoparib and olaparib, are orally available therapeutics that target DNA repair, and have demonstrated efficacy in breast cancer patients with mutations in BRCA1/2 (BRCA-MUT) in the metastatic and adjuvant settings. Clinical trials have tested the combination of a low potency PARPi (veliparib) with carboplatin. It would be ideal we could better select a TNBC patient subpopulation that could best benefit from PARPi. Furthermore, it is plausible that more potent PARPi can be used in combination with carboplatin to inhibit the development of distant metastasis for these hard-to-treat cancers.
To better select which TNBC patients will benefit from PARPi, we have derived a 63-gene signature. Using a panel of TNBC cell lines, we quantified the 53BP1 response (marker of double-strand breaks) of three PARPi, veliparib, olaparib, and talazoparib using single-cell analysis. We then categorized our cell lines as sensitive or resistant and created a fold-change gene expression metric that was applied to the entire transcriptome. In combination with a curated gene list associated with PARPi or DNA damage response, we performed a gene set and pathway enrichment analysis, to identify statistically significant pathways with 63 associated genes. Using a previously published cohort of 7 PDX tumors, we found that our gene signature predicted response to olaparib with a high overall accuracy of 86%. We also identified our gene signature amongst 45% of untreated TNBC patients.
To better understand the combination of a potent PARPi, talazoparib and carboplatin, we determined that their combination resulted in a synergistic effect in 9/10 TNBC cell lines. We compared concomitant talazoparib and carboplatin, sequential talazoparib then carboplatin (seq TC), and sequential carboplatin followed by talazoparib in a BRCA wild-type TNBC MDAMB231 cell line and orthotopic xenograft. Paradoxically, we found that the seq TC approach demonstrated the greatest reduction, 70.4% (P<0.0001) in cell migration, 76.3% in liver metastasis (P = 0.02), and 56.4% in lung metastasis (P < 0.0001). Taken together, it is plausible that PARPi will be effective amongst a larger TNBC subpopulation, of which our 63-gene signature could be used a tool for improved selection. Furthermore, the use of PARPi in combination with carboplatin is an effective approach which can be used to inhibit the development of metastatic disease.

 

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