Bellmunt Joaquim, Werner Lillian, Bamias Aristotle, Fay André P, Park Rachel S, Riester Markus, Selvarajah Shamini, Barletta Justine A, Berman David M, de Muga Silvia, Salido Marta, Gallardo Enrique, Rojo Federico, Guancial Elizabeth A, Bambury Richard, Mullane Stephanie A, Choueiri Toni K, Loda Massimo, Stack Edward, Rosenberg Jonathan
Bladder Cancer Center, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medical Oncology, University Hospital de Mar-IMIM, Barcelona, Spain.
Cancer Med. 2015 Jun;4(6):844-52. doi: 10.1002/cam4.432. Epub 2015 Feb 26.
We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥ 2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2-positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.
我们评估了来自西班牙（N = 111）和希腊（N = 102）两个队列中接受铂类化疗患者的原发性肿瘤。对转移性尿路上皮癌（UC）患者进行了HER2状态检测（免疫组化（IHC）评分为3+或荧光原位杂交（FISH）比率≥2.2），包括免疫组化、荧光原位杂交、DNA拷贝数、mRNA表达及突变状态，并评估其对生存的影响。通过热点测序确定ERBB2突变。使用NanoString计数法评估mRNA表达。通过Cox回归模型评估总生存期（OS）与HER2状态的相关性。对含有HER2 V777L的NIH-3T3细胞进行生长、侵袭及HER2激酶激活评估。总体而言，西班牙队列中22%和希腊队列中4%的患者通过免疫组化检测显示HER2染色为3+。西班牙队列中20%和希腊队列中4%的患者检测到FISH扩增。FISH与免疫组化之间的kappa系数为0.47。在单因素分析（西班牙P = 0.34；希腊P = 0.11）或多因素分析（西班牙P = 0.49；希腊P = 0.12）中，HER2状态与总生存期均无相关性。HER2阳性肿瘤比HER2阴性肿瘤表达更高水平 的HER2 mRNA（P < 0.001）。在两名（2%）患者中鉴定出HER2突变（V777L和L755S）。对V777L的体外分析导致NIH-3T3细胞转化，从而使生长增加、在软琼脂上的侵袭能力增强以及HER2激酶组成性激活。总之，原发性肿瘤中HER2过表达或扩增并不能预测转移性UC患者的总生存期。不同人群的HER2阳性率可能不同。需要对进行基因组筛查的患者开展进一步试验，以评估UC中针对HER2的治疗方法。
