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Abstract：
Triple-negative breast cancer (TNBC) is usually an aggressive disease with a poor prognosis and limited treatment options. The neurotrophic tyrosine receptor kinase (NTRK) gene fusions are cancer type-agnostic emerging biomarkers approved by the Food and Drug Administration (FDA), USA, for the selection of patients for targeted therapy. The main aim of our study was to investigate the frequency of NTRK aberrations, i.e. fusions, gene copy number gain, and amplification, in a series of TNBC using different methods. A total of 83 TNBCs were analyzed using pan-TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR), and RNA-based next-generation sequencing (NGS). Of 83 cases, 16 showed pan-TRK positivity although no cases had NTRK-fusions. Indeed, FISH showed four cases carrying an atypical NTRK1 pattern consisting of one fusion signal and one/more single green signals, but all cases were negative for fusion by NGS and RT-PCR testing. In addition, FISH analysis showed six cases with NTRK1 amplification, one case with NTRK2 copy number gain, and five cases with NTRK3 copy number gain, all negative for pan-TRK IHC. Our data demonstrate that IHC has a high false-positive rate for the detection of fusions and molecular testing is mandatory; there is no need to perform additional molecular tests in cases negativity for NTRK by IHC. In conclusion, the NTRK genes are not involved in fusions in TNBC, but both copy number gain and amplification are frequent events, suggesting a possible predictive role for other NTRK aberrations.
摘要：
三阴性乳腺癌（TNBC）通常是一种侵袭性疾病，预后差，治疗选择有限。神经营养酪氨酸受体激酶（NTRK）基因融合是由食品和药物管理局（FDA）批准的癌症类型不可知的新兴生物标志物。美国,用于选择患者进行靶向治疗。我们研究的主要目的是调查NTRK像差的频率，即融合，基因拷贝数增加，和放大，在一系列TNBC中使用不同的方法。使用pan-TRK免疫组织化学（IHC）分析了总共83个TNBC，荧光原位杂交（FISH），实时聚合酶链反应(RT-PCR),和基于RNA的下一代测序（NGS）。83例,16显示pan-TRK阳性，尽管没有NTRK融合。的确,FISH显示4例携带由一个融合信号和一个/多个单一绿色信号组成的非典型NTRK1模式，但通过NGS和RT-PCR检测，所有病例均为融合阴性。此外,FISH分析显示6例NTRK1扩增,一个具有NTRK2拷贝数增益的情况，5例NTRK3拷贝数增加，泛TRKIHC均为阴性。我们的数据表明，IHC对融合体的检测具有很高的假阳性率，并且必须进行分子检测；如果IHC对NTRK阴性，则无需进行其他分子检测。总之,NTRK基因不参与TNBC的融合，但是拷贝数增加和扩增都是频繁的事件，提示其他NTRK像差可能的预测作用。
