Homologous recombination deficiency (HRD) score predicts response to platinum-based chemotherapies in Chinese high grade serous ovarian cancer patients (188)

Abstract

<b>Objectives:</b> Homologous recombination repair deficiency (HRD), as a major feature of high-grade serous ovarian, is associated with the efficacy of PARP inhibitor (PARPi) therapy. Tumors present with HRD are characterized by a defect in DNA double-strand break repair, which is thought to render particularly sensitive to inter-strand cross-linking agents, including platinum analogs. However, whether HRD status confers sensitivity to platinum-based chemotherapies in high-grade serous ovarian patients remains poorly defined. <b>Methods:</b> In this study, we used the machine learning method to build a genomic scar (GS) model to predict HRD, which takes different types of chromosomal copy numbers into consideration for the calculation of genomic instability. GS score ≥50 was defined as HRD positive, accounting for 94.5% of <i>BRCA</i>-deficient events. HRD score, consisting of heterozygous (LOH), telomeric allelic imbalance (TAI), and Large-scale transition (LST), was also determined (HRD-positive [score ≥42] versus HRD-negative [score <42]), and both GS score and HRD score impacts on clinical efficacy were explored. <b>Results:</b> A total of 94 high-grade serous ovarian patients who received first-line platinum-based chemotherapy but no further PARPi maintenance therapy was picked out and analyzed for the predictive value of GS score and HRD score in platinum-based chemotherapy efficacy. GSS-positive was observed in 78/94 (82.9%) patients, and HRD-positive was observed in 74/94 (78.7%) patients, concordance between GS score and HRD score was 91%. Progression-free survival (PFS) (GSS: HR: 0.604; p=0.00082; HRD: HR: 0.64; p=0.00134), overall survival (OS) (GSS: HR: 0.482; p=0.00155; HRD: HR: 0.496; p=0.00231), and platinum-free interval (PFI) (GSS: HR: 0.621; p=0.00204; HRD: HR: 0.664; p=0.00482) were significantly longer in both GS-positive and HRD-positive groups (Figure 1). In <i>BRCA</i>-wildtype patients, survival differences were also seen in GSS-positive versus GSS-negative (p=0.007674) and HRD-positive versus HRD-negative (p=0.017588) populations (Figure 2). Platinum-resistant patients with a PFI of less than six months show a significantly lower GSS-positive rate and HRD-positive rate than platinum-sensitive patients (PFI>6 months) (Figure 2).Fig. 1 <b>Conclusions:</b> HRD status identifies high-grade serous ovarian patients and remains a significant predictor of response to platinum-based chemotherapy. GSS showed high concordance with the HRD score, which implied the high robustness of the GS model.