High-grade serous ovarian cancer (HGSC) is a highly metastatic cancer with the majority of patients presenting at advanced stages. Over the last few decades, the overall survival and standard of care for patients have not significantly improved and there are limited targeted treatment options for patients. Although we have learned much about the genomic characteristics of HGSC primary tumors, there has been a lack of characterization of metastatic tumors. In order to identify genetic markers of metastasis and poor prognosis, we have characterized the genomic and transcriptomic alterations of primary and metastatic tumors in HGSC patients with different survival outcomes. In this study, matched normal tissue, primary, and metastatic tumors from 23 HGSC short-term (ST) survivors (OS <3.5 years) and 14 long-term (LT) survivors (OS >5 years) underwent whole-exome and RNA sequencing. We compared somatic mutations, copy number alternations, mutational burdens, differential expression, homologous recombination (HRD) scores, and gene fusion predictions between the primary and metastatic tumors of the ST and LT survival groups. We confirmed previously published findings that tumors of LT survivors were more likely to have BRCA1 alterations, higher HRD scores, and more copy-altered segments when compared to tumors of ST survivors. We identified 10,124 somatic mutations in the tumors of LT survivors and 13,599 somatic mutations in ST survivors. There was a higher percentage of shared variants between the primary and metastatic tumors for ST survivors compared to LT survivors. ST survivors also had a greater mutational burden than LT survivors. We observed little differences in differential expression between primary and metastatic tumors, but we did observe unique clustering between the transcriptomes of LT and ST survivors’ tumors. Although there was no significant difference between the number of gene fusions predicted between primary and metastatic tumors, there was a total of 1,218 gene fusions predicted in ST survivors’ tumors, which was significantly more than the 240 gene fusions predicted in LT survivors. The ST primary tumor group had the highest number of predicted gene fusions. Interestingly, we observed that patients with HRD-positive primary tumors but HRD-negative metastatic tumors had significantly shorter overall survival compared to matched tumor pairs with no, or very little, difference in HRD scores. This finding suggests that differences in HRD scores between primary and metastatic tumors in HGSC patients may correlate with survival. Overall, we observed similar genomic and transcriptomic findings in the landscape between primary and metastatic tumors in HGSC patients and identified genetic characteristics specific to tumors of LT and ST survivors.

Citation Format: Emilee N. Kotnik, Nicholas C. Spies, Christopher A. Miller, Tiandao Li, Matthew Inkman, Jin Zhang, Christopher A. Maher, Carolyn K. McCourt, Premal H. Thaker, Andrea R. Hagemann, David G. Mutch, Matthew A. Powell, Katherine C. Fuh. Characterization of primary-metastasis pairs in high-grade serous ovarian cancer with short- and long-term survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A17.