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2022-RA-1148-ESGO Mutational signature 3 identifies HRD and predicts clinical outcome in advanced high grade serous ovarian cancer
  1. Heidi Koskela1,2,
  2. Yilin Li3,
  3. Anni Virtanen3,4,
  4. Titta Joutsiniemi1,2,
  5. Taru Muranen3,
  6. Jaana Oikkonen3,
  7. Sampsa Hautaniemi3 and
  8. Johanna Hynninen1,2
  1. 1University of Turku, Turku, Finland
  2. 2Turku University Hospital, Turku, Finland
  3. 3University of Helsinki, Helsinki, Finland
  4. 4Helsinki University Hospital, Helsinki, Finland


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).

Abstract 2022-RA-1148-ESGO Figure 1

Progression-free survival

Abstract 2022-RA-1148-ESGO Table 1

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.

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