Background:Folate receptor alpha (FRα) is a glycosylphosphatidylinositol-anchored membrane protein encoded by theFOLR1gene. Its overexpression in various cancers, including ovarian carcinoma, makes it a promising target for antibody-drug conjugates (ADC). Mirvetuximab soravtansine-gynx, an FRα-targeting ADC, has been approved by the FDA and EMA for the treatment of FRα-positive, platinum-resistant ovarian cancer. In the United States, patient selection is tied to the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay, an immunohistochemical (IHC) test that identifies tumors with ≥75% moderate-to-strong membrane staining. However, in the European Union, no specific IHC test is mandated, and alternative antibodies are frequently used in routine pathology, necessitating validation of their diagnostic performance.Methods and Results:We report the results of the first interlaboratory proficiency trial on FRα testing conducted by the German Quality Assurance Initiative in Pathology (QuIP®). Sixty-eight pathology institutes participated across internal and open trials using a variety of antibodies and staining platforms. The VENTANA FOLR1 RxDx Assay demonstrated the highest reliability, with 83% of participating laboratories achieving a successful result. In contrast, alternative clones such as BN3.2 (Leica/Novocastra) and EPR20277 (Abcam) showed substantially weaker staining intensity, lower concordance with reference values, and success rates of only 22–25%, while other antibodies failed entirely. Problem analysis revealed that failures with the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay were mainly due to interpretative challenges, whereas weak staining was the predominant issue with alternative clones. Participation in a preparatory online seminar improved pass rates, underscoring the importance of training.Conclusions:These findings highlight the critical importance of standardized, validated assays for FRα detection to ensure accurate patient selection for targeted therapies. The study emphasizes the need for further optimization of alternative antibodies before clinical implementation.
背景：叶酸受体α（FRα）是一种由FOLR1基因编码的糖基磷脂酰肌醇锚定膜蛋白。其在多种癌症（包括卵巢癌）中的过表达使其成为抗体偶联药物（ADC）的理想靶点。Mirvetuximab soravtansine-gynx是一种靶向FRα的ADC，已获美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）批准用于治疗FRα阳性、铂类耐药的卵巢癌。在美国，患者选择与VENTANA FOLR1 (FOLR1-2.1) RxDx检测法相关联，这是一种免疫组织化学（IHC）检测，用于识别≥75%细胞膜呈中至强染色的肿瘤。然而，在欧盟，并未强制要求使用特定的IHC检测方法，常规病理学中经常使用其他抗体，因此需要验证其诊断性能。 方法与结果：我们报告了由德国病理学质量保证倡议组织（QuIP®）开展的首次FRα检测实验室间能力验证试验的结果。68家病理学研究机构参与了内部和公开试验，使用了多种抗体和染色平台。VENTANA FOLR1 RxDx检测法显示出最高的可靠性，83%的参与实验室获得了成功结果。相比之下，其他克隆抗体如BN3.2（Leica/Novocastra）和EPR20277（Abcam）显示出明显较弱的染色强度、与参考值的一致性较低，成功率仅为22-25%，而其他抗体则完全失败。问题分析显示，VENTANA FOLR1 (FOLR1-2.1) RxDx检测法的失败主要源于判读挑战，而其他克隆抗体的主要问题则是染色偏弱。参加预备在线研讨会提高了通过率，凸显了培训的重要性。 结论：这些发现强调了标准化、经过验证的FRα检测方法对于确保精准选择靶向治疗患者的至关重要性。该研究强调，在临床应用前需要进一步优化其他抗体。
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