AUTHOR=Kim Yoo-Na , Kim Kyeongmin , Joung Je-Gun , Kim Sang Wun , Kim Sunghoon , Lee Jung-Yun , Park Eunhyang 

TITLE=RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer

JOURNAL=Frontiers in Oncology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1351778

DOI=10.3389/fonc.2024.1351778

ISSN=2234-943X

ABSTRACT=<sec><title>Objective</title><p>Effective functional biomarkers that can be readily used in clinical practice to predict poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity are lacking. With the widespread adoption of PARPi maintenance therapy in ovarian cancer, particularly in patients with <italic>BRCA</italic> mutation or HR deficiencies, accurately identifying <italic>de novo</italic> or acquired resistance to PARPi has become critical in clinical practice. We investigated RAD51 immunohistochemistry (IHC) as a functional biomarker for predicting PARPi sensitivity in ovarian cancer.</p></sec><sec><title>Methods</title><p>Ovarian cancer patients who had received PARPi and had archival tissue samples prior to PARPi exposure (“pre-PARPi”) and/or after progression on PARPi (“post-PARPi”) were selected. RAD51 IHC expression was semi-quantitatively evaluated using the H-score in geminin (a G2/S phase marker)- and γH2AX (a DNA damage marker)-positive tissues. A RAD51 H-score of 20 was used as the cutoff value.</p></sec><sec><title>Results</title><p>In total, 72 samples from 56 patients were analyzed. The median RAD51 H-score was 20 (range: 0–90) overall, 10 (0–190) in pre-PARPi samples (n = 34), and 25 (1–170) in post-PARPi samples (n = 19). Among patients with <italic>BRCA</italic> mutations, RAD51-low patients had better progression-free survival (PFS) after PARPi treatment than RAD51-high patients (<italic>P</italic> = 0.029). No difference was found in PFS with respect to the genomic scar score (<italic>P</italic> = 0.930). Analysis of matched pre- and post-PARPi samples collected from 15 patients indicated an increase in the RAD51 H-score upon progression on PARPi, particularly among pre-PARPi low-RAD51-expressing patients.</p></sec><sec><title>Conclusion</title><p>RAD51 is a potential functional IHC biomarker of <italic>de novo</italic> and acquired PARPi resistance in <italic>BRCA</italic>-mutated ovarian cancer and can be used to fine-tune ovarian cancer treatment.</p></sec>