Replication stress marker phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination-proficient ovarian cancer

Schab, A.; Compadre, A.; Drexler, R.; Loeb, M.; Rodriguez, K.; Brill, J.; Harrington, S.; Sandoval, C.; Sanders, B.; Kuroki, L.; McCourt, C.; Hagemann, A. R.; Thaker, P.; Mutch, D.; Powell, M.; Serra, V.; Hagemann, I. S.; Walts, A. E.; Karlan, B. Y.; Orsulic, S.; Fuh, K.; Sun, L.; Verma, P.; Lomonosova, E.; Zhao, P.; Khabele, D.; Mullen, M. M.

doi:10.1101/2024.11.21.624682

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bioRxiv · 10.1101/2024.11.21.624682

Replication stress marker phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination-proficient ovarian cancer

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Abstract

BackgroundOvarian cancer treatment includes cytoreductive surgery, platinum-based chemotherapy, and often poly (ADP-ribose) polymerase (PARP) inhibitors. Homologous recombination (HR)-deficiency is a well-established predictor of therapy sensitivity. However, over 50% of HR-proficient tumors also exhibit sensitivity to standard-of-care treatments. Currently, there are no biomarkers to identify which HR-proficient tumors will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. MethodsWe evaluated phospho-RPA2-T21 (pRPA2) foci via immunofluorescence as a potential biomarker of replication stress in formalin-fixed, paraffin-embedded tumor samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort: n = 31, validation cohort: n = 244) or PARP inhibitors (n = 87). Recurrent tumors (n = 37) were also analyzed. pRPA2 scores were calculated using automated imaging analysis. Samples were defined as pRPA2-High if > 16% of cells had [≥] 2 pRPA2 foci. ResultsIn the discovery cohort, HR-proficient, pRPA2-High tumors demonstrated significantly higher rates of pathologic complete response to platinum chemotherapy than HR-proficient, pRPA2-Low tumors. In the validation cohort, patients with HR-proficient, pRPA2-High tumors had significantly longer survival after platinum treatment than those with HR-proficient, pRPA2-Low tumors. Additionally, the pRPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent tumor samples. ConclusionOur study underscores the importance of considering replication stress markers alongside HR status in therapeutic planning. Our work suggest that this assay could be used throughout a patients treatment course to expand the number of patients receiving effective therapy while reducing unnecessary toxicity.

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Schab, A., Compadre, A., Drexler, R., Loeb, M., Rodriguez, K., Brill, J., Harrington, S., Sandoval, C., Sanders, B., Kuroki, L., McCourt, C., Hagemann, A. R., Thaker, P., Mutch, D., Powell, M., Serra, V., Hagemann, I. S., Walts, A. E., Karlan, B. Y., Orsulic, S., Fuh, K., Sun, L., Verma, P., Lomonosova, E., Zhao, P., Khabele, D., Mullen, M. M.. 2024-11-25. Replication stress marker phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination-proficient ovarian cancer. https://doi.org/10.1101/2024.11.21.624682

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