Exploring the mechanism of PARPi resistance in ovarian cancer by integrated analyze of pre- and post-progression samples in 5 patients.

person Qingli Li Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China info_outline Liang Song, Xiaojuan Lin, Wenhao Zhang, Peng Cheng, Changbin Zhu, Rutie Yin, Qingli Li

Authors person Qingli Li Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China info_outline Liang Song, Xiaojuan Lin, Wenhao Zhang, Peng Cheng, Changbin Zhu, Rutie Yin, Qingli Li Organizations Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China, Amoy Diagnostics Co., Ltd., Xiamen, China, Department of Gynecology and Obstetrics, and Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China Abstract Disclosures Research Funding Other Government Agency Background: PARP inhibitors (PARPi) have been widely used in the treatment of homologous recombination repair-deficient tumors. Comprehensive investigations on the resistance mechanisms of PARPi and tumor microenvironment alterations after PARPi therapy are largely insufficient. Methods: 5 ovarian cancer patients (pts) treated with PARPi at West China Second University Hospital were enrolled in this study (Ethical Lot Number: 20200076). Clinicopathological information of the pts are shown in table below. Paired PARPi treatment-naive surgical samples (TNS) and the biopsy samples that progressed after PARPi maintenance therapy (PPS) were obtained. Multi-omic profiling was conducted by an NGS panel (Master Panel, AmoyDx) containing DNA exon regions of 563 genes and RNA expression of 1831 genes analyzing genetic mutations and dynamics of gene expression profile in these paired tumor samples. Results: Median duration of treatment with PARPi was 18 months (11-22). Comprehensive genomic profiling discovered MYC amplification (n = 3), ZFHX4 mutation (n = 2) and IDH1 mutation (n = 1) in PPS. One PPS harbored simultaneous amplification of PDCD1 , FGF3 , MYC , FGF19 and ZFHX4 mutation. In addition, BRCA1 intron11: c.4096+1G > T mutation was detected in one PPS carrying germline BRCA1 mutation (E1066*), which putatively resulted in restoration of BRCA1 function. At RNA level, single-sample enrichment analysis showed that B cells, T cells, and co-activation factors were significantly up-regulated in PPS. In addition, expression of CXCL13 and activation of CCL19/21-CCR7 axis were significantly increased, which indicated a PARPi-triggered “hot” immune-microenvironment. Moreover, immune-checkpoint TIGIT was significantly upregulated, paved the way for immunotherapy. Nevertheless, stromal remodeling, and tumor proliferation signatures were also up-regulated in PPS. In parallel, cancer-related pathways, PI3K/AKT, Epithelial-Mesenchymal transition, cell-cycle as well as G2M checkpoint were observed in the pathway enrichment analysis, which further verified the aforementioned findings. Conclusions: This small sample size study confirmed the complexity of the resistance mechanisms to PARPi, including BRCA reversion mutation, oncogene activation and bypass signaling activation. The activation of both positive and negative immune regulators in the tumor microenvironment shed light on future clinical management for patients with PARPi resistance. Pts No. Pathology Stage R0 resection Germline pathogenic/likely pathogenic mutation Lines of chemotherapy before PARPi PARPi Duration of treatment with PARPi (mo) 1 HGSOC IIIc No BRCA1 3 Fluzoparib 22 2 CCOC Ic Yes PMS2 3 Olaparib 15 3 HGSOC IIIc Yes BRCA1 2 Fluzoparib 19 4 HGSOC IIIc Yes BRCA1 3 Olaparib 11 5 HGSOC IIIc No BRCA1 1 Olaparib 18 HGSOC: high grade serious ovarian cancer; CCOC: clear cell ovarian cancer.