Background: Homologous recombination repair (HRR) pathway deficiency (HRD) is deeply involved in the tumorigenesis and progression of high-grade serous ovarian carcinoma (HGSOC) as well as in the sensitivity to platinum chemotherapy drugs. Until now, the proposed cutoff value for the HRD score, determined by calculating genomic scar signature scores associated with HRD, namely, the loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST), has been ≥ 42 based on a combined dataset of HGSOC and breast cancer. In this study, we propose a rational method to classify HGSOC based on HRD status and investigated its clinical significance.

Methods: We obtained data from The Cancer Genome Atlas (TCGA) on HGSOC and determined the HRD score as the sum of LOH, TAI, and LST scores. We then investigated the relationships among the score, genetic alterations in HRR-related genes, and the clinical data.

Results:BRCA1/2 mutations were enriched in the group with HRD scores ≥ 63. BRCA1/2 mutations represented 38% of the cases with HRD scores ≥ 63 (49/128), 10% with HRD scores between 42 and 62 (12/118), and 10% with HRD scores 41 and below (5/50); no enrichment of BRCA1/2 mutation cases with HRD scores from 42 to 62 was observed compared with those with scores ≤ 41. Compared with the groups with scores ≤ 62, this group had a good prognosis (p < 0.0001); we thus considered HRD scores ≥ 63 to be the best cutoff point for identifying HRD cases in HGSOC. Among the other HRR pathway gene mutations, only CHEK1 homozygous deletions and PTEN homozygous deletions were associated with high HRD scores (p = 0.0038 and p = 0.035, respectively). In terms of promoter methylation, BRCA1 methylations and RAD51C methylations were associated with high HRD scores (p < 0.0001 and p = 0.029, respectively). Classification of HGSOC cases by the HRD status revealed a better prognosis for HRD cases caused by genetic alterations (HRD-G) than those caused by epigenetic changes (HRD-E), those caused by undetermined reasons (HRD-U), and non-HRD cases (p < 0.0001). A combined analysis of HRD status and residual tumor after primary debulking surgery revealed that, among cases without macroscopic residual tumors, 11 of 12 HRD-G cases survived after the median observation period of 6.6 years, showing remarkably higher survival rates than HRD-E, HRD-U, and non-HRD cases (p = 0.0059).

Conclusion: HRD score ≥ 63 is an optimal cut-off to define HRD in HGSOC. HGSOC can be classified into subtypes with different prognoses according to HRD status. This classification could be useful for personalized HGSOC treatment.

Citation Format: Noriomi Matsumura, Hisamitsu Takaya, Shiro Takamatsu, Hidekatsu Nakai. Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma [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 A49.