Cappuzzo F, Toschi L, Domenichini I, Bartolini S, Ceresoli G L, Rossi E, Ludovini V, Cancellieri A, Magrini E, Bemis L, Franklin W A, Crino L, Bunn P A, Hirsch F R, Varella-Garcia M
Department of Medicine/Medical Oncology and Pathology, University of Colorado Cancer Center, Campus Box 8117; PO Box 6511, Aurora, CO 80045, USA.
Br J Cancer. 2005 Dec 12;93(12):1334-40. doi: 10.1038/sj.bjc.6602865.
In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH+ pattern was significantly associated with female gender (P=0.02) and never smoking history (P=0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P=0.04) than patients with HER3- tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P=0.03) and time to progression (7.7 vs 2.7 months, P=0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3- tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.
在非小细胞肺癌（NSCLC）中，对酪氨酸激酶抑制剂（TKIs）的敏感性与表皮生长因子受体（EGFR）的激活突变和基因组扩增有关。临床前数据表明，HER3过表达会增加对TKIs的敏感性。本研究共纳入82例接受吉非替尼（250 mg）治疗的NSCLC患者，这些患者此前已通过荧光原位杂交（FISH）和DNA测序评估了EGFR和HER2状态，并通过免疫组织化学评估了磷酸化Akt状态，通过FISH检测了HER3基因组扩增情况。高多体性和基因扩增的患者被视为HER3 FISH阳性（+）。HER3 FISH+模式与女性性别（P=0.02）和从不吸烟史（P=0.02）显著相关。HER3+肿瘤患者（26.8%）的疾病进展时间显著长于HER3-肿瘤患者（3.7 vs 2.7，P=0.04），但缓解率或生存率无显著差异。EGFR+/HER3+肿瘤患者的客观缓解率（36.4 vs 9.9%，P=0.03）和疾病进展时间（7.7 vs 2.7个月，P=0.03）高于EGFR-和/或HER3-肿瘤患者，但生存期无显著延长。EGFR+肿瘤患者中，根据HER3状态未观察到缓解差异。HER2+/HER3+肿瘤患者与HER2-和/或HER3-肿瘤患者的结局相似。HER3+/P-Akt+肿瘤患者与HER3-和/或P-Akt-肿瘤患者之间未观察到显著不同的临床终点。HER3的基因组扩增不是晚期NSCLC患者对TKI治疗反应或耐药的标志物。
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