Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Department of Clinical Haematology and Medical Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
Prostate. 2023 Feb;83(2):169-178. doi: 10.1002/pros.24450. Epub 2022 Oct 19.
Genomic defects in DNA-damage repair (DDR) mechanisms have been proposed to affect the radiosensitivity of prostate cancers. In this study, we intended to evaluate the prevalence of genetic alterations in a cohort of metastatic castration-resistant prostate cancer (mCRPC) patients undergoing radioligand therapy (RLT) with prostate-specific membrane antigen (PSMA)-inhibitors as well as the impact of such mutations on treatment outcomes.
Data of consecutive mCRPC patients from 2017 to 2021 who were treated with PSMA-RLT and underwent next-generation sequencing (NGS) were collected and analyzed for response and survival outcomes.
In 95 patients of mCRPC treated with PSMA-RLT, 15 patients (median age: 66 years, range: 50-73 years; [ Lu]Lu-PSMA-617, n = 12; [ Ac]Ac-PSMA-617, n = 3) underwent NGS. The median progression-free survival (PFS) of this cohort was 3 months (95% confidence interval: 1.6-4.4 months). On NGS, 21 genetic alterations were reported in 10/15 (67%) patients, of which 13 were DDR-associated alterations involving the genes: ATM (n = 3), BRCA2 (n = 3), TP53 (n = 2), PTEN (n = 2), FANCD2 (n = 1), FANCM (n = 1), and NBN (n = 1). Overall, 5/15 (33%) patients harbored six pathogenic variants (BRCA2, n = 2; ATM, n = 1; TP53, n = 1; PTEN, n = 2). No significant difference was noted for the biochemical response, radiological response, PFS, and overall survival between the patients with and without genetic alterations.
Patients of mCRPC undergoing PSMA-RLT were frequently seen to harbor DDR-associated aberrations, albeit with no significant impact on treatment outcomes. Large prospective trials comparing PSMA-RLT-related outcomes in DDR-deficient and -proficient patients are required to bring out the differences, if any, in a more observable manner.
DNA 损伤修复 (DDR) 机制中的基因组缺陷被认为会影响前列腺癌的放射敏感性。在这项研究中，我们旨在评估接受前列腺特异性膜抗原 (PSMA)-抑制剂放射性配体治疗 (RLT) 的转移性去势抵抗性前列腺癌 (mCRPC) 患者队列中遗传改变的流行率，以及这些突变对治疗结果的影响。
收集了 2017 年至 2021 年期间接受 PSMA-RLT 治疗并接受下一代测序 (NGS) 的连续 mCRPC 患者的数据，并对其反应和生存结果进行了分析。
在接受 PSMA-RLT 治疗的 95 例 mCRPC 患者中，15 例患者（中位年龄：66 岁，范围：50-73 岁；[Lu]Lu-PSMA-617，n=12；[Ac]Ac-PSMA-617，n=3）接受了 NGS。该队列的中位无进展生存期 (PFS) 为 3 个月（95%置信区间：1.6-4.4 个月）。在 NGS 上，10/15（67%）患者报告了 21 种遗传改变，其中 13 种涉及 DDR 相关改变的基因：ATM（n=3）、BRCA2（n=3）、TP53（n=2）、PTEN（n=2）、FANCD2（n=1）、FANCM（n=1）和 NBN（n=1）。总体而言，5/15（33%）患者携带六种致病性变异（BRCA2，n=2；ATM，n=1；TP53，n=1；PTEN，n=2）。有和没有遗传改变的患者之间在生化反应、放射学反应、PFS 和总生存期方面没有显著差异。
接受 PSMA-RLT 的 mCRPC 患者常伴有 DDR 相关异常，但对治疗结果没有显著影响。需要进行大型前瞻性试验，比较 DDR 缺陷和功能正常的患者接受 PSMA-RLT 相关结果，以更明显地显示出差异（如果有）。
