Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum, and survival.
Up to 50% of epithelial ovarian cancers (EOC) display defects in the homologous recombination (HR) pathway. We sought to determine the ramifications of the homologous recombination-deficient (HRD) status on the clinicopathologic features, chemotherapy response, and survival outcomes of patients with EOCs. HR status was determined in primary cultures from ascitic fluid in 50 chemotherapy-naïve patients by a functional RAD51 immunofluorescence assay and correlated with in vitro sensitivity to the PARP inhibitor (PARPi), rucaparib. All patients went on to receive platinum-based chemotherapy; platinum sensitivity, tumor progression, and overall survival were compared prospectively in HR-competent versus HRD patients. Compared with HR-competent patients, the HRD group was predominantly serous with a higher median CA125 at presentation. HRD was associated with higher ex vivo PARPi sensitivity and clinical platinum sensitivity. Median follow-up duration was 14 months; patients in the HRD group had lower tumor progression rates at 6 months, lower overall/disease-specific death rates at 12 months, and higher median survival. We therefore suggest that HRD as predicted by a functional RAD51 assay correlates with in vitro PARPi sensitivity, clinical platinum sensitivity, and improved survival outcome.
Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, N Ireland, United Kingdom.
Asima
A
Mukhopadhyay
Elizabeth R
ER
Plummer
Ahmed
A
Elattar
San
S
Soohoo
Bisha
B
Uzir
Jennifer E
JE
Quinn
W Glenn
WG
McCluggage
Perry
P
Maxwell
Harriet
H
Aneke
Nicola J
NJ
Curtin
Richard J
RJ
Edmondson
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D059765:Homologous Recombination; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016190:Carboplatin; D017239:Paclitaxel