Advances in PARP inhibitors for the treatment of breast cancer.
BACKGROUND
Poly(ADP-Ribose) polymerases (PARPs) are one of the important components of base excision repair pathway for single strand DNA breaks. Currently accepted hypothesis for the mechanism of action for PARP inhibitors in tumors with homologous recombination deficiency is synthetic lethality, as the simultaneous blockage of both pathways prevents the tumor cells from repairing DNA damage. Other proposed mechanisms include PARP trapping, defective BRCA1 and POLQ recruitment to sites of DNA repair. Breast cancer subgroups with germline BRCA mutations or non-mutational functional defects in BRCA proteins exemplify potential targets for PARP inhibitors.


METHODS
Promising results have been achieved with PARP inhibitors in BRCA associated cancers, particularly in ovarian and breast cancer. Olaparib is the only PARP inhibitor approved by FDA in the treatment of patients with germline BRCA mutated advanced ovarian cancer pretreated with ≥3 prior lines of chemotherapy. In this article, we reviewed the current status of PARP inhibitors, completed and ongoing trials, safety and resistance issues in patients with breast cancer.


CONCLUSIONS
PARP inhibitors show promise in cancers with BRCA mutation and in the treatment of sporadic cancers with defective homologous recombination. Predictors of response, strategies to overcome resistance, combination with other chemotherapies and targeted agents, optimum dose and schedule of administration should be investigated in future trials.
a Department of Preventive Oncology , Hacettepe University Institute of Cancer , Ankara 06100 , Turkey.
Omer
O
Dizdar
b Department of Medical Oncology , Izmir University Faculty of Medicine , Izmir 35540 , Turkey.
Cagatay
C
Arslan
c Department of Medical Oncology , Hacettepe University Institute of Cancer , Ankara 06100 , Turkey.
Kadri
K
Altundag
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002986:Clinical Trials as Topic; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
BRCA1; BRCA2; PARP inhibitor; breast cancer; homologous recombination; synthetic lethality