Primary platinum resistance and immune exclusion in ovarian carcinomas with high expression of the homologous recombination mediator RAD51

Hoppe, M. M.; Tan, T. Z.; Lie, S.; Lim, S.; Yeong, J. P.; Wardyn, J. D.; Jaynes, P.; Lim, D. G.; Pang, B. N.; Karnezis, A.; Chiu, D.; Leung, S.; Huntsman, D. G.; Sedukhina, A. S.; Sato, K.; Kaye, S.; Choi, H.; Patel, N.; Brown, R.; Pitt, J. J.; Tan, D. S.; Jeyasekharan, A.

doi:10.1101/2020.06.09.137612

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bioRxiv · 10.1101/2020.06.09.137612

Primary platinum resistance and immune exclusion in ovarian carcinomas with high expression of the homologous recombination mediator RAD51

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Abstract

BackgroundHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. The homologous recombination (HR) mediator RAD51, however, is commonly overexpressed, potentially driving unregulated HR. Due to non-quantitative measurements and heterogeneous cohorts, the clinical relevance of RAD51 expression in ovarian cancer is unclear. MethodsFluorescent immunohistochemistry and multispectral imaging were used to quantitate RAD51 expression, in relation to other markers, in independent cohorts of ovarian carcinomas from British Columbia Cancer (BCC n=284) and the phase III SCOTROC4 trial (n=268). Independent cohorts (TCGA n=566, GSE9891 n=267, GSE26712 n=185 and GSE3149 n=146) were used for mRNA expression and immune infiltration analyses. ResultsRAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in both BCC and SCOTROC4. The negative prognostic significance of high RAD51 was primarily evident in cases classified "HRD negative" by the Myriad genomic scar assay. Unexpectedly, overexpression of RAD51 in ovarian cancer cell lines did not affect sensitivity to platinum or PARP inhibitors, but modified the expression of immune-regulatory genes. Accordingly, tumours with high RAD51 mRNA showed consistent changes in immunomodulatory transcripts across four independent ovarian cancer cohorts. In-situ multiplexed imaging confirmed that high RAD51 tumours correlated with tumour exclusion of cytotoxic-T-cells, possibly explaining their poor outcomes after chemotherapy. ConclusionsHigh RAD51 expression, in conjunction with a HRD score <42, identifies a subgroup of EOC cases with platinum resistance and an immune excluded tumour microenvironment. Tumours with high RAD51 may require alternate or additional adjuvant therapeutic strategies to overcome immune exclusion. Statement of Translational RelevanceHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. Currently, methods to identify patients who do poorly on first-line platinum based chemotherapy in ovarian cancer represent an unmet clinical need. In this report we show that RAD51 expression can identify patients with primary platinum resistance in two large cohorts, including a unique phase-III trial of carboplatin as adjuvant monotherapy. The clinical relevance of a positive genomic scar HRD score, a biomarker for assessing HRD status, in predicting benefit to PARP inhibitors has been established following recent phase 3 trials in first line and 2nd line maintenance treatment of ovarian cancer. Our findings suggest that HRD negative ovarian tumours may be further stratified by RAD51 expression status in the context of platinum sensitivity, and may serve to guide future trials of HRD targeted agents.

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Hoppe, M. M., Tan, T. Z., Lie, S., Lim, S., Yeong, J. P., Wardyn, J. D., Jaynes, P., Lim, D. G., Pang, B. N., Karnezis, A., Chiu, D., Leung, S., Huntsman, D. G., Sedukhina, A. S., Sato, K., Kaye, S., Choi, H., Patel, N., Brown, R., Pitt, J. J., Tan, D. S., Jeyasekharan, A.. 2020-06-09. Primary platinum resistance and immune exclusion in ovarian carcinomas with high expression of the homologous recombination mediator RAD51. https://doi.org/10.1101/2020.06.09.137612

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