Modification of Homologous Recombination Deficiency Score Threshold and Association with Long-Term Survival in Epithelial Ovarian Cancer

Abstract

New therapies, such as poly-ADP ribose polymerase inhibitors (PARPi), and immunotherapy treatments have generated great interest in enhancing individualized molecular profiling of epithelial ovarian cancer (EOC) to improve management of the disease. In EOC patients, putative biomarkers for homologous recombination deficiency (HRD), microsatellite instability (MSI), and tumor mutational burden (TMB) were characterized and correlated with survival outcomes. A series of 300 consecutive EOC patients were enrolled. Patients underwent neoadjuvant chemotherapy (n = 172) or primary cytoreductive surgery (n = 128). Molecular profiling and survival analyses were restricted to the primary cytoreductive surgery cohort due to tissue availability. All patients underwent germline testing for HRD- and MSI-related gene mutations. When sufficient tissue was available, screening for somatic BRCA1/2 mutations, BRCA1 promoter methylation, HRD score (a measure of genomic instability), MSI, and TMB testing were performed. HRD score ≥33 was associated with improved overall survival on multivariable analysis. In the era of biomarker-driven clinical care, HRD score ≥33 may be a useful adjunctive prognostic tool and should be evaluated in future studies to predict PARPi benefits.

Keywords: epithelial ovarian cancer; homologous recombination deficiency; homologous recombination deficiency score; microsatellite instability; survival; tumor mutational burden.

Figure 1

Flow diagram of patient population.

Figure 2

HRD score values and their associated HR defects in high-grade serous histology (n = 74). HR = homologous recombination. HRD = homologous recombination deficiency. HRD score cut-off threshold was defined as ≥42 (red solid line). HRD score values above this threshold line were considered high HRD scores (HR deficient tumors) and values below the threshold line were considered low HRD scores (HR proficient tumors). An HRD score cut-off threshold ≥33 (red dotted line) was also evaluated. Please note that values on the y-axis have been scattered to allow easier visualization of the HRD score datapoints. There is no variable on the y-axis.

Figure 3

HRD score values and their associated HR defects in non-high-grade serous histology (n = 21). HR = homologous recombination. HRD = homologous recombination deficiency. HRD score cut-off threshold was defined as ≥42 (red solid line). HRD score values above this threshold line were considered high HRD scores (HR deficient tumors) and values below the threshold line were considered low HRD scores (HR proficient tumors). An HRD score cut-off threshold ≥33 (red dotted line) was also evaluated. Please note that values on the y-axis have been scattered to allow easier visualization of the HRD score datapoints. There is no variable on the y-axis.

Figure 4

Overall survival based on HRD score threshold. (a) Overall survival based on HRD score threshold of 42; (b) overall survival based on HRD score threshold of 33.