Abstract 2811: High IFN/STAT-related gene expression is associated with sensitivity to PARP inhibitors of triple negative breast cancer
Authors: Cairo Stefano , Déas Olivier , Tran Truong-an , Judde Jean-Gabriel 
Published: August 2018

Triple negative breast cancer (TNBC) comprises 15-20% of all breast cancers, and carries increased risk of distant metastasis, early relapse and short post-recurrence survival. TNBC shares clinical and pathological features with hereditary BRCA1/2-related breast cancers. In TNBCs, besides mutation-associated BRCA inactivation occurring by loss of heterozygosity (LOH) in about 15% of the cases, dysregulation in the homologous-recombination (HR)-dependent DNA-repair pathway has been attributed to a number of mechanisms. PARP1 and PARP2, two important regulators of the DNA base-excision-repair pathway, have emerged as therapeutic targets for TNBC. Indeed, a subset of TNBC patients is responsive to PARP inhibitors (PARPi), a class of novel therapeutic agents that inhibits the function of several PARP family members. Pathogenic BRCA1/2 mutations, and other genomic markers have been proposed as molecular markers to identify tumors with homologous recombination deficiency (HRD) that are more likely to be sensitive to PARPi. However, these tests lack specificity as less than half of TNBC patients harboring BRCA-mutated or HRD-positive tumors are responsive to PARP inhibitors, and a number of TNBC patients without BRCA1/2 mutations are responsive to PARP inhibitors.

In the present study, we investigated the antitumor activity of PARPi in a panel of 28 TNBC patient-derived xenograft PDX models. Responses were correlated with BRCA1/2, with HRD status and with other HRD markers, and GSEA analysis was run to compare gene expression profile of PARP inhibitor-sensitive vs resistant TNBC PDXs.

Among the gene signatures differentially expressed we identified the IFN/STAT signature as upregulated in tumors sensitive to PARPi. We previously described that TNBC PDXs that respond to a genotoxic stress induce activation of the IFN/STAT pathway. Therefore we hypothesized that a significant fraction of tumors scoring HRD positive (by BRCA mutation or genomic scarring assay) may have reverted back to a phenotype of HR competency, making them refractory to PARP inhibition. In this scenario, IFN/STAT-related gene expression might be a feature of HRD-positive tumors in which HR deficiency has not been compensated and is still effective, resulting in PARP inhibitor sensitivity. Inclusion of this parameter strongly ameliorated the predictive power of the HRD assay, with decreased rate of false-positives (28.6% for IFN/STAT signature + HRD versus 52.9% for HRD alone) and overall misclassification reduced to only 5/28 PDXs (17.6% for IFN/STAT signature + HRD versus 32.1% for HRD alone).

This study suggests that high IFN/STAT-related gene expression can be a strong marker of persistent tumor instability and improve the performance of HRD-based PARPi efficacy predictive scores.

Citation Format: Stefano Cairo, Olivier Déas, Truong-an Tran, Jean-Gabriel Judde. High IFN/STAT-related gene expression is associated with sensitivity to PARP inhibitors of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2811.