7.4　PARP Inhibitor Targeted Therapy

In cells with defective BRCA，other DNA repair pathways become more important due to homologous recombination disorders.Among them，poly ADP ribosylation，which is involved in poly（ADP-ribosyltransferase-1）（BRCA-1），is a key component in the base excision repair pathway.Deficient BRCA gene function leads to defects in cell homologous recombination repair.Inhibition of BRCA-1 will block another major repair pathway of cells，leading to apoptosis after cell damage.This is called synthetic lethality.The clinicopathological features of TNBC are similar to those of BRCA-associated breast cancer.Studies have shown that PARP-1 expression rate in TNBC can reach 80%，so theoretically PARP-1 may become a powerful target of TNBC.Studies have shown that resistance to triple-negative breast cancer treatment is associated with DNA damage repair.PARP inhibitors can enhance the efficacy of radiotherapy and alkylating agents and platinum-based chemotherapy by inhibiting DNA damage repair in tumor cells and promoting apoptosis in tumor cells.Therefore，PARP inhibitors are particularly important for triple-negative breast cancer，especially metastatic triple-negative breast cancer.Olapani，as a currently marketed PARP inhibitor，has been approved for the treatment of relapsed and refractory metastatic ovarian cancer，and studies have shown that it also plays an important role in BRCA-mutant triple-negative breast cancer.

The 2009 ASCO Annual Meeting announced the results of Phase Ⅱ clinical trials of the PARP inhibitor Iniparib.A total of 123 patients with metastatic TNBC were enrolled and randomized into two groups：the treatment group（GCI group）received gemcitabine plus carboplatin plus inipanib，and the control group（GC group）received gemcitabine plus carboplatin.The results showed that there was a statistically significant difference between the treatment group and the control group.The clinical benefit rate was 56%vs 34%（P=0.01），and the total effective rate was 52%and 32%，respectively（P=0.02）.The OS was 12.3 months vs 7.7 months（HR=0.57，P=0.01）.However，such significant differences did not appear in the similarly designed Inipani Phase Ⅲ clinical trials，and the OS and PFS of the GCI and GC groups did not reach the expected significant differences.Whether Inipani is a true.PARP inhibitor has been questioned.Due to the failure of Inipani and another PARP inhibitor，veliparib，the study of PARP inhibition has been stagnant for a long time.However，the 2017 ACSO meeting reported on the results of the Olympiad study，reaffirming the therapeutic value of PARP inhibitors for breast cancer.In this study，302 patients with advanced breast cancer with BRCA mutations or suspected adverse mutations were randomized to at least 2 chemotherapy regimens and were randomized to the Olaparib group and the single-agent chemotherapy selected by the physician.Median PFS For 7 months vs 4.2 months，the effective rates were 59.9%and 28.8%，respectively，and the difference was statistically significant.Olapani became the first PARP inhibitor approved for BRCA-mutant breast cancer，which led to the development of multiple new drug clinical studies of PARP inhibitors.(https://www.daowen.com)

With the further understanding of the molecular characteristics of TNBC，FGFR inhibitors，mTORinhibitors，Src inhibitors（Dasatinib），hedgehog and NOTCH pathways may become TNBC molecular targets.Most of these drugs are currently in the early stage of clinical development.Determining whether they have a unique effect on TNBC will take a considerable amount of time.