Phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination–proficient ovarian cancer
Angela Schab, Amanda Compadre, Rebecca Drexler, Megan Loeb, Kevin Rodriguez, Joshua Brill, Shariska Harrington, Carmen Sandoval, Brooke Sanders, Lindsay Kuroki, Carolyn McCourt, Andrea R. Hagemann, Premal Thaker, David Mutch, Matthew Powell, Violeta Serra, Ian S. Hagemann, Ann E. Walts, Beth Y. Karlan, Sandra Orsulic, Katherine C. Fuh, Lulu Sun, Priyanka Verma, Elena Lomonosova, Peinan Zhao, Dineo Khabele, Mary M. Mullen
Angela Schab, Amanda Compadre, Rebecca Drexler, Megan Loeb, Kevin Rodriguez, Joshua Brill, Shariska Harrington, Carmen Sandoval, Brooke Sanders, Lindsay Kuroki, Carolyn McCourt, Andrea R. Hagemann, Premal Thaker, David Mutch, Matthew Powell, Violeta Serra, Ian S. Hagemann, Ann E. Walts, Beth Y. Karlan, Sandra Orsulic, Katherine C. Fuh, Lulu Sun, Priyanka Verma, Elena Lomonosova, Peinan Zhao, Dineo Khabele, Mary M. Mullen
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Clinical Research and Public Health Clinical Research Oncology

Phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination–proficient ovarian cancer

Abstract

BACKGROUND Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly(ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR) deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSCs also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response.METHODS We evaluated phospho–RPA2-T21 (p-RPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort, n = 31; validation cohort, n = 244) or PARP inhibitors (n = 63). Recurrent HGSCs (n = 38) were also analyzed. p-RPA2 score was calculated using automated imaging analysis.RESULTS Samples were defined as p-RPA2-high if more than 16% of cells had ≥2 p-RPA2 foci on automated analysis. In the discovery cohort, HR-proficient, p-RPA2-high HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, p-RPA2-low HGSCs. In the validation cohort, patients with HR-proficient, p-RPA2-high HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, p-RPA2-low HGSCs. Additionally, the p-RPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples.CONCLUSION Our study underscores the importance of considering replication stress markers, such as p-RPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity.FUNDING The Reproductive Scientist Development Program, GOG Foundation, Pilot Translational and Clinical Studies function of the Washington University Institute of Clinical and Translational Sciences, the Foundation for Barnes-Jewish Hospital, Washington University School of Medicine Dean’s Scholar Program, The Cancer Biology Pathway Training Grant (5T32CA113275-17), The Lucy, Anarcha, and Betsey (L.A.B.) Award from the Department of Obstetrics and Gynecology at Washington University School of Medicine, and Veterans Affairs Office of Research and Development (I01BX006020).

Authors

Angela Schab, Amanda Compadre, Rebecca Drexler, Megan Loeb, Kevin Rodriguez, Joshua Brill, Shariska Harrington, Carmen Sandoval, Brooke Sanders, Lindsay Kuroki, Carolyn McCourt, Andrea R. Hagemann, Premal Thaker, David Mutch, Matthew Powell, Violeta Serra, Ian S. Hagemann, Ann E. Walts, Beth Y. Karlan, Sandra Orsulic, Katherine C. Fuh, Lulu Sun, Priyanka Verma, Elena Lomonosova, Peinan Zhao, Dineo Khabele, Mary M. Mullen

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Figure 1

p-RPA2 score predicts therapy response and survival in patients with RAD51-high HGSCs treated with platinum chemotherapy in a discovery cohort.

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p-RPA2 score predicts therapy response and survival in patients with RAD...
(A) RAD51 score, p-RPA2 score, chemotherapy response score (CRS), and platinum sensitivity in patients with HGSCs before neoadjuvant chemotherapy. p-RPA2 score is defined as the percentage of cells having ≥2 p-RPA2 foci. Dashed black line indicates manual quantification 20% cutoff, which delineates p-RPA2-high and p-RPA2-low HGSCs. All foci were counted in n > 100 cells per experiment. Technical replicates were performed for 30% of samples. (B) Representative images of DAPI and p-RPA2 and overlay of DAPI/p-RPA2 in patient-derived FFPE HGSC samples; images taken at ×63 original magnification. (C) Kaplan-Meier curves evaluating progression-free survival in patients with HGSCs stratified by p-RPA2 score (n = 27, hazard ratio 0.7, 95% CI 0.3–1.7, P = 0.4). (D) Kaplan-Meier curves evaluating progression-free survival in patients with HGSCs stratified by RAD51 and p-RPA2 scores. (E) Proportion of RAD51-high HGSCs that had a CRS of 3 stratified by p-RPA2 score (P = 0.03). (F) Kaplan-Meier curves evaluating overall survival in patients with RAD51-high HGSCs stratified by p-RPA2 score (n = 19, hazard ratio 0.08, 95% CI 0.01–0.64, P = 0.02). *P < 0.05, by Student’s 2-tailed t test.