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Abstract
Introduction/Background Approximately 50% of high grade serous ovarian cancers (HGSC) are considered to have homologous recombination deficiency (HRD). Tumors with HRD are markedly sensitive to platinum-based chemotherapy and Poly-ADP Ribose Polymerase inhibitors (PARPi). Signature 3 (Sig3) is a mutational signature that is strongly associated with BRCA 1/2 mutations and considered as HRD signature. In the current analysis, we aim to evaluate whether whole genome sequencing (WGS) -based Sig3-test can reliably predict clinical outcome.
Methodology This prospective trial was conducted in Turku University Hospital, Finland. Patients (n=116) with HGSC and stages III-IV were included. DNA was extracted from fresh tissue samples (n=279). Signature analyses were performed by fitting COSMIC v3.2 reference signature 3 to the WGS data of samples with matched normals, and cosine similarity was used to compare mutational profiles to the reference signature. Patients were divided into two subgroups: positive Sig3 status (Sig3+) or negative Sig3 status (Sig3-). Sig3+ was defined as HRD.
Results In all, 56 patients were Sig3+, and 60 patients were Sig3-. Sig3- patients were older (the median age was 72 vs. 65 years, p=0.001). Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with Sig3+ (figure 1). The median PFS was 22.1 months for Sig3+ patients and 12.2 months for Sig3- patients. The median OS was 49.8 months and 31.4 months, respectively. Sig3- patients had worse primary therapy outcome (table 1). Sig3- predicted worse PFS (HR 2.20, CI 1.39–3.46, p<0.001) in multivariate Cox regression analysis. Additionally, NACT patients had worse PFS compared to PDS patients (HR 2.97, CI 1.86–34.74, p<0.001).
Progression-free survival
Responses to 1st line treatment
Conclusion Mutational signature 3 test can identify reliable cancers with HRD. Sig3 status predicts treatment outcome and overall survival. Further studies are needed to evaluate clinical validity of Sig3-based assay for predicting PARPi benefit.