Abstract：
Targetable NTRK gene fusions can be detected across tumor types using methodologies such as pan-TRK IHC, DNA or RNA NGS testing, or FISH. Challenges for implementation of clinical testing for NTRK fusions may arise due to the range in NTRK fusion prevalence across tumors, endogenous levels of TRK expression in tissues, and the large number of potential fusion partners. In this study, we examined our experience evaluating driver mutation negative lung, urothelial or cholangiocarcinoma cases, in addition to cases with positive, equivocal, or weak staining by pan-TRK IHC for NTRK fusions. 63/127 (49.6%) of these cases were positive for pan-TRK IHC, of which 71.4% showed weak or focal staining, potentially due to physiologic or non-specific TRK expression. Of these 127 cases, 4 harbored a NTRK fusion (1 fusion was seen in two separate samples from the same patient) as confirmed by RNA fusion panel testing. Pan-TRK IHC was positive in 1 case with TPM3-NTRK1 fusion, equivocal in 1 case with GOLGA4-NTRK3 fusion, and negative in 2 samples with ADAM19-NTRK3 fusion. Our findings show that we were able to successfully identify NTRK fusions that resulted in targeted therapy. However, our results suggest limited sensitivity of pan-TRK IHC for NTRK3 fusions, and that the reduced specificity for pan-TRK IHC in tumors with physiologic or non-specific TRK expression, results in false positive samples that require confirmatory testing by RNA based NGS.
摘要：
使用pan-TRKIHC等方法可以在肿瘤类型中检测到可靶向的NTRK基因融合体，DNA或RNANGS测试,或者鱼。实施NTRK融合的临床测试的挑战可能由于NTRK融合在肿瘤中的流行范围而出现。组织中TRK表达的内源性水平，以及大量潜在的融合伙伴。在这项研究中,我们检查了我们评估驱动突变阴性肺的经验，尿路上皮或胆管癌病例，除了阳性的病例，模棱两可,或通过pan-TRKIHC对NTRK融合体的弱染色。其中63/127（49.6%）为泛TRK免疫组化阳性，其中71.4%表现为微弱或局灶性染色，可能是由于生理或非特异性TRK表达。在这127个案例中，如通过RNA融合组测试所证实的,图4中所示的具有NTRK融合体(在来自同一患者的两个单独的样品中观察到1个融合体)。Pan-TRK免疫组化阳性1例TPM3-NTRK1融合,1例GOLGA4-NTRK3融合不一致，在2个ADAM19-NTRK3融合样品中呈阴性。我们的研究结果表明，我们能够成功地鉴定出导致靶向治疗的NTRK融合。然而,我们的结果表明pan-TRKIHC对NTRK3融合的敏感性有限，并且在具有生理性或非特异性TRK表达的肿瘤中pan-TRKIHC的特异性降低，结果假阳性样品需要通过基于RNA的NGS进行验证性测试。
