Abstract 2P
Background
PARP inhibitors (PARPi) maintenance has become standard therapy in ovarian cancer. Strong anti-tumor effect was demonstrated especially in homologous recombination defects (HRD) tumors. However, systematic clinical study on PARPi resistance mechanisms and molecular changes of tumor is still lacking.
Methods
In this study (ethics number: 20200076), 14 ovarian cancer patients who were treated with PARPi at West China Second University Hospital were enrolled. PARPi treatment-naive samples (PNS, n = 12) and post-PARPi progression samples (PPS, n = 14) were acquired. Two next-generation sequencing (NGS) panels (Master panel, 563 genes for exons of DNA plus 1831 genes for RNA; HRD panel, 70,000 SNPs for HRD score evaluation, Amoydx) were used to analyze gene variation, expression, and HRD score changes in tumors.
Results
Total 14 resistant-related DNA alternation were identified. In 12 BRCA1/2 deficient cases, 4 (25%) BRCA1/2 restoration mutation were observed in PPS. Other resistant-related gene alternation included FGFR AMP (amplification, 16.7%) MYC AMP (16.7%), CCND1 AMP (16.7%), and RB1 loss (8.3%). 21.4% (3/14) cases harbored 2 or more resistance-related mutation. Upregulation of PIK3CA, MAPK, and Wnt signaling was observed at the RNA level in four cases lacking resistance-related DNA alterations. When compared with PNS, HRD scores and tumor mutation burden (TMB) were significantly elevated in PPS. Patients with high HRD scores in PPS had shorter PFS in PARPi rechallenge. DNA repair was up regulated in PPS. JAK, Apoptosis and MAPK pathways were down regulated in PPS. Cell cycle and other cancer related pathways upregulated after PARPi resistance. NK-cell/ T-cell and B-cell scores were up regulated in PPS.
Conclusions
Resistance mechanism of PARPi is complex. BRCA restoration mutation is a frequent cause of PARPi resistance. PARPi resistance could be driven without DNA mutation. Up regulating DNA damage repair and down regulating of apotosis could promotes tumor survival. The predictive value of HRD score for PARPi response was not applicable in the PARPi-treated samples. Tumor microenvironment could be changed and beneficial to immunotherapy after PARPi.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Peng, T. Sun, C. Zhu: Financial Interests, Institutional, Full or part-time Employment: Amoy Diagnostics Co., Ltd. All other authors have declared no conflicts of interest.