Establishing the homologous recombination score threshold in metastatic prostate cancer patients to predict the efficacy of PARP inhibitors

被引：3

作者：

Zhao, Diwei ^{[1
,2
]}

Wang, Anqi ^{[1
,3
]}

Li, Yuanwei ^{[1
,2
]}

Cai, Xinyang ^{[1
,2
]}

Zhao, Junliang ^{[1
,2
]}

Zhang, Tianyou ^{[4
]}

Zhao, Yi ^{[5
]}

Dong, Yu ^{[5
]}

Zhou, Fangjian ^{[1
,2
]}

Li, Yonghong ^{[1
,2
]}

Wang, Jun ^{[1
,2
]}

机构：

[1] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr, Guangzhou, Peoples R China

[2] Sun Yat Sen Univ, Dept Urol, Canc Ctr, Guangzhou, Peoples R China

[3] Sun Yat Sen Univ, Canc Ctr, Dept Musculoskeletal Oncol, Guangzhou, Peoples R China

[4] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Urol, Guangzhou, Peoples R China

[5] Precis Sci Beijing Co Ltd, Beijing, Peoples R China

来源：

JOURNAL OF THE NATIONAL CANCER CENTER | 2024年 / 4卷 / 03期

基金：

中国国家自然科学基金;

关键词：

Homologous recombination deficiency score; Threshold; PARP inhibitors; Homologous recombination repair pathway; mutation; BRCA; DNA-REPAIR;

D O I：

10.1016/j.jncc.2024.05.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: The homologous recombination deficiency (HRD) score serves as a promising biomarker to identify patients who are eligible for treatment with PARP inhibitors (PARPi). Previous studies have suggested a 3-biomarker Genomic Instability Score (GIS) threshold of >= 42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer. However, the GIS threshold for prostate cancer (PCa) is still lacking. Here, we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients. Methods: A total of 181 patients with metastatic castration-resistant PCa were included in this study. Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair (HRR) genes and copy number variation (CNV) analysis. The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors. The relationship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed. Results: Genomic testing was succeeded in 162 patients. In our cohort, 61 patients (37.7%) had HRR mutations (HRRm). BRCA mutations occurred in 15 patients (9.3%). The median HRD score was 4 (ranged from 0 to 57) in the total cohort, which is much lower than that in breast and ovarian cancers. Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores. CNV occured more frequently in patients with HRRm. The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores >= 43. In the 16 patients who received PARPi in our cohort, 4 patients with a high HRD score achieved an objective response rate (ORR) of 100% while 12 patients with a low HRD score achieved an ORR of 8.3%. Progression-free survival (PFS) in HRD high patients was longer compared to HRD low patients, regardless of HRRm. Conclusions: A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study. Future studies are needed to further verify this threshold.

引用

页码：280 / 287

页数：8

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