Abstract ES12-3: Clinically relevant biomarkers of PARP1 inhibitor resistance and indicators of targeted combinatorial treatments

Tumors with defective DNA repair by the homologous recombination repair (HRR) pathway are exquisitely sensitive to DNA damaging agents and to novel agents that block parallel pathways, including PARP inhibitors (PARPi). PARPi have been approved for the treatment of metastatic ovarian cancer (OvC) or breast cancer (BC). Currently used selection biomarkers to enrich the population of patients (pt) most likely to respond, namely the platinum-sensitive or BRCA1/2-mutated patients (pts), have limited predictive capacity. There is a need for more specific biomarkers to guide personalized treatment. Genomic scars/signatures have been proposed as putative biomarkers associated with DNA repair deficiency. A major limitation of these assays is the lack of specificity in HRR-altered tumors once they have restored the HRR function as mechanism of drug resistance. Functional assays are therefore needed to assess the actual status of tumor HRR, both in BRCA1/2-mutated pts and in BRCA1/2-wt, to identify tumors with germline/somatic HRR deficiency that could benefit of PARPi treatment. In this sense, the RAD51 foci assay is a functional and dynamic biomarker of HRR that correlates with PARPi response. In this educational talk, we will review the current knowledge on PARPi sensitivity and resistance in breast cancer, response biomarkers and the potential of targeting the replication stress response to revert PARPi resistance, namely using WEE1 or ATR inhibitors (WEE1i, ATRi). Our preclinical work using patient-derived tumor xenoimplant models (PDX) from triple negative breast cancer (TNBC) identified selection biomarkers for WEE1i or ATRi as single agents or in combination with PARP1/2 inhibitors, and highlights the potential of DNA damage repair inhibitors for the treatment of TNBC, an approach currently being tested in the clinic. Citation Format: V Serra. Clinically relevant biomarkers of PARP1 inhibitor resistance and indicators of targeted combinatorial treatments [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES12-3.