Background: Metastatic prostate cancers frequently harbour pathogenic aberrations in Homologous Recombination Repair (HRR) genes that confer sensitivity to PARP inhibitors (PARPi). Therefore, accurate identification of all eligible patients is needed. The development of a circulating tumour DNA (ctDNA) testing alternative is promising as genomic testing of archived tissue leads to a failure rate of up to 30–40% in prostate cancer. Methods: This was a bi-institutional retrospective cohort study of patients with metastatic prostate cancer treated at the Jewish General Hospital or the McGill University Health Center, Montreal, Canada, between 2021 and 2023. Molecular data and treatment information were abstracted from a chart review. Chi-square, Fisher’s exact test, and Mann–Whitney tests were used to assess differences between groups. Results: We identified 484 metastatic prostate cancer patients. Somatic and germline testing for HRR was performed in 55.4% (n= 268) and 20% (n= 97) patients, respectively. Somatic testing was performed on tissue (n= 192, 71.6%) or ctDNA from liquid biopsies (n= 18, 6.7%) or both (n= 58, 21.7%). Pathogenic somatic HRR alterations were detected in 48 patients (17.9%). BRCA2 was the most frequent (n= 17), followed by ATM (n= 11), then CHEK2 (n= 5). Amongst patients with germline testing, 13/97 (13.4%) had pathogenic alterations predicted to lead to deficient HRR, mostly BRCA2 (n= 9), and three had detectable BRCA2 in tissue. Dual testing modality (tissue+ctDNA) significantly enhanced the detection rate of HRR alterations 19/58 (32.7%) vs. 29/210 (13.8%) for single testing modality (tissue or ctDNA),p= 0.008. The rate of inconclusive results was significantly lower in dual testing modality 0/58 (0%) vs. 25/210 in single testing modality (11.9%),p= 0.003. Amongst the 14 patients who had discordant results between liquid and tissue tests, HRR abnormalities were more frequently identified in ctDNA (n= 11) vs. tissue (n= 3). Patients who had HRR deficiency detected only in ctDNA had older tissue samples (median 5.6 years) compared to those who had deficient HRR detected only in tissue (median 0.2 years;p= 0.14). Conclusions: These data highlight a potential role in implementing liquid biopsy—especially in patients who only have older archival tissue available or failed tissue testing—to improve the detection rate of deficient HRR. Our ongoing prospective study will further validate whether the addition of liquid biopsy can identify more patients who are eligible to receive precision therapies by increasing the rate of detection of HRR deficiency compared to routine tissue testing alone.
背景：转移性前列腺癌常携带同源重组修复（HRR）基因的致病性异常，这些异常使其对PARP抑制剂（PARPi）敏感。因此，需要准确识别所有符合条件的患者。开发循环肿瘤DNA（ctDNA）检测作为替代方案前景广阔，因为对存档组织进行基因组检测在前列腺癌中的失败率高达30-40%。 方法：这是一项双机构回顾性队列研究，纳入了2021年至2023年间在加拿大蒙特利尔犹太总医院或麦吉尔大学健康中心接受治疗的转移性前列腺癌患者。通过病历审查提取分子数据和治疗信息。使用卡方检验、Fisher精确检验和Mann-Whitney检验评估组间差异。 结果：我们确定了484名转移性前列腺癌患者。分别有55.4%（n=268）和20%（n=97）的患者接受了HRR的体细胞检测和胚系检测。体细胞检测在组织样本（n=192，71.6%）或液体活检的ctDNA（n=18，6.7%）上进行，或两者兼有（n=58，21.7%）。在48名患者（17.9%）中检测到致病性体细胞HRR改变。BRCA2最常见（n=17），其次是ATM（n=11），然后是CHEK2（n=5）。在接受胚系检测的患者中，13/97（13.4%）存在预计会导致HRR缺陷的致病性改变，主要为BRCA2（n=9），其中三人在组织中检测到BRCA2。双重检测模式（组织+ctDNA）显著提高了HRR改变的检出率，为19/58（32.7%），而单一检测模式（组织或ctDNA）为29/210（13.8%），p=0.008。双重检测模式的不确定结果率显著更低，为0/58（0%），而单一检测模式为25/210（11.9%），p=0.003。在14名液体和组织检测结果不一致的患者中，HRR异常更常在ctDNA中检测到（n=11），而在组织中检测到较少（n=3）。与仅在组织中检测到HRR缺陷的患者（中位数0.2年）相比，仅在ctDNA中检测到HRR缺陷的患者其组织样本更陈旧（中位数5.6年；p=0.14）。 结论：这些数据突显了实施液体活检的潜在作用——特别是对于仅有较陈旧存档组织可用或组织检测失败的患者——以提高HRR缺陷的检出率。我们正在进行的前瞻性研究将进一步验证，与单独进行常规组织检测相比，增加液体活检是否能通过提高HRR缺陷的检出率，识别出更多有资格接受精准治疗的患者。
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