Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study).
Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study).
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DOI：
10.1093/annonc/mdv501
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Tamura T
中科院分区：
文献类型：
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作者：
Takeuchi K;Togashi Y;Kamihara Y;Fukuyama T;Yoshioka H;Inoue A;Katsuki H;Kiura K;Nakagawa K;Seto T;Maemondo M;Hida T;Harada M;Ohe Y;Nogami N;Yamamoto N;Nishio M;Tamura T
我们前瞻性地表明，当间变性淋巴瘤激酶(ALK)免疫组织化学(IHC)足够敏感并得到适当解释时，它可以作为ALK抑制剂治疗的独立诊断。我们的数据将进一步推广和推广IHC，用于筛查将受益于ALK抑制剂治疗的患者，并为此目的削减时间和金钱成本。间变性淋巴瘤激酶(ALK)融合需要准确有效地检测，以进行ALK抑制剂治疗。荧光原位杂交(FISH)仍然是参考试验。虽然越来越多的数据支持ALK免疫组织化学(IHC)与FISH高度一致，但IHC筛查仍需临床和前瞻性验证。在AF-001JP对阿莱替尼的试验中，436名患者通过IHC(n=384)筛查了ALK融合，FISH(n=181)、多重RT-PCR(n=68)或两者兼而有之(n=16)。IHC结果用iScore评分。ALK融合阳性137例，阴性250例。由于RT-PCR的样本中未证实癌细胞的存在，因此无法确定49例患者的ALK融合阴性。IHC与FISH的符合率为99.4%(173/174)。所有41名接受iScore 3并进入II期的患者肿瘤减少了至少30%，总有效率为92.7%。两名具有非典型FISH模式的IHC阳性患者对碱性磷酸酶抑制剂治疗有反应。细胞减少率与IHC染色强度无关。我们的研究表明：(I)当足够敏感和适当地解释时，IHC可以作为ALK抑制剂治疗的独立诊断指标；(Ii)当非典型FISH模式伴有IHC阳性时，患者应被视为ALK抑制剂治疗的候选患者；(Iii)ALK融合的表达水平与ALK抑制剂的反应水平无关，因此不是患者选择所必需的。JAPICCTI-101264(本研究已在日本药物信息中心注册)。
We prospectively showed that when anaplastic lymphoma kinase (ALK) immunohistochemistry (IHC) is sensitive enough and appropriately interpreted, it can be a stand-alone diagnostic for ALK inhibitor therapies. Our data will further spread and promote IHC for the screening of patients who will benefit from ALK inhibitor therapy, and cut the time and money costs for that purpose. Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).