Evans Elizabeth, Dholakia Jhalak, Abraham Jim, Hinton Andrew, Zhang Jian, Xiu Joanne, Maney Todd, Oberley Matt, Thacker Premal, Herzog Thomas J, Spetzler David, Arend Rebecca C
Mercy Hospital Coletta Cancer Center, Oklahoma City, OK, USA.
East Carolina University Health, Greenville, NC, USA.
Gynecol Oncol. 2025 Jun;197:139-145. doi: 10.1016/j.ygyno.2025.04.586. Epub 2025 May 8.
BACKGROUND/OBJECTIVES: Homologous recombination repair deficiency (HRD) is frequently detected in gynecological cancers and is associated with sensitivity to poly-ADP ribose polymerase inhibition (PARPi). BRCA1/2 mutations have been approved as biomarkers for PARPi therapy, along with genomic patterns such as genomic loss of heterozygosity (gLOH) and large-scale transitions (LSTs). Clinical applications of various HRD assays are still under investigation. Here we validate the performance of a novel HRD assay based on whole-exome sequencing (WES).
WES was used to evaluate gLOH, LST, and BRCA mutations and this data was compared to standard assays. An optimized genomic scar score (GSS) was based on combined gLOH and LST. A comprehensive HRD score was then developed, combining GSS and BRCA status. Survival data from 1661 PARPi-treated ovarian cancer patients was queried to optimize GSS and HRD scores associated with PARPi response.
A comparison of WES results to the OncoScan CNV assay and Myriad MyChoice assay showed high concordance for LOH values and GSS values, respectively. Median overall survival in PARPi-treated patients was 50.8 months for GSS-high, BRCA1/2-mut, 42.7 months for GSS-high, BRCA1/2-WT, and 36.6 months for GSS-low, BRCA1/2-WT patients with significant differences between each group. Combining the BRCA1/2-mut and WT GSS-high groups resulted in a median OS value of 47.8 months, significantly higher than the GSS-low BRCA1/2-WT group.
The use of a WES assay to assess BRCA results, along with a GSS method incorporating gLOH and LST, produced a HRD test that is predictive for PARPi therapy.
背景/目的：同源重组修复缺陷（HRD）在妇科癌症中经常被检测到，并且与对聚-ADP核糖聚合酶抑制（PARPi）的敏感性相关。BRCA1/2突变已被批准作为PARPi治疗的生物标志物，以及诸如基因组杂合性缺失（gLOH）和大规模转变（LSTs）等基因组模式。各种HRD检测方法的临床应用仍在研究中。在此，我们验证了一种基于全外显子测序（WES）的新型HRD检测方法的性能。
使用WES评估gLOH、LST和BRCA突变，并将此数据与标准检测方法进行比较。优化后的基因组疤痕评分（GSS）基于合并的gLOH和LST。然后开发了一个综合HRD评分，将GSS和BRCA状态相结合。查询了1661例接受PARPi治疗的卵巢癌患者的生存数据，以优化与PARPi反应相关的GSS和HRD评分。
将WES结果与OncoScan CNV检测方法和Myriad MyChoice检测方法进行比较，结果显示分别在LOH值和GSS值方面具有高度一致性。接受PARPi治疗的患者中，GSS高、BRCA1/2突变组的中位总生存期为50.8个月，GSS高、BRCA1/2野生型组为42.7个月，GSS低、BRCA1/2野生型组为36.6个月，各组之间存在显著差异。将BRCA1/2突变和野生型GSS高组合并后，中位总生存期值为47.8个月，显著高于GSS低的BRCA1/2野生型组。
使用WES检测方法评估BRCA结果，以及结合gLOH和LST的GSS方法，产生了一种可预测PARPi治疗效果的HRD检测方法。
