使用 PARP 抑制剂 (PARPi) 对以同源重组 (HR) 途径中关键参与者缺失为特征的肿瘤（通常称为“BRCAness”）观察到的合成致死效应，一直引起肿瘤学的高度关注。虽然 BRCA 是乳腺癌、卵巢癌、前列腺癌和胰腺癌的一个公认特征，但我们最近的研究结果表明，高达 15% 的结直肠癌 (CRC) 也存在 HR 通路缺陷，这为创新治疗策略提供了有希望的机会。结直肠癌患者。我们开发了一种名为 HRDirect 的新工具，它建立在 HRDetect 算法的基础上，能够从无参考肿瘤样本中预测 HR 缺陷 (HRD)。我们使用匹配的乳腺癌和结直肠癌患者样本验证了 HRDirect。随后，我们通过将其与其他两种商业化验进行比较，评估了其预测 PARP 抑制剂奥拉帕尼反应的功效：淘大诊断的 AmoyDx HRD 和 Illumina NGS 技术的 TruSight Oncology 500 HRD (TSO500-HRD) 组合。虽然这三种方法都成功识别了对 PARPi 最敏感的 CRC 模型，但与 AmoyDX 和 TSO500-HRD 相比，HRDirect 在区分耐药模型方面表现出卓越的精度，后者在敏感细胞和耐药细胞之间表现出重叠的分数。此外，我们建议将 HRDirect 评分与 ATM 和 RAD51C 免疫组织化学分析相结合，作为我们“复合生物标志物方法”的一部分，以增强 HRD 肿瘤的识别，对 CRC 个性化治疗产生直接的转化和临床影响。© 2024。作者。

The synthetic lethal effect observed with the use of PARP inhibitors (PARPi) with tumors characterized by the loss of key players in the homologous recombination (HR) pathway, commonly referred to as "BRCAness", is maintaining high interest in oncology. While BRCAness is a well-established feature in breast, ovarian, prostate, and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HR deficiency (HRD) from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology 500 HRD (TSO500-HRD) panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM and RAD51C immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.© 2024. The Author(s).