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人表皮生长因子受体2（HER2）过表达和扩增作为结直肠癌潜在的治疗靶点：对参与QUASAR、FOCUS和PICCOLO结直肠癌试验的3256例患者的分析

HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

作者信息

Richman Susan D, Southward Katie, Chambers Philip, Cross Debra, Barrett Jennifer, Hemmings Gemma, Taylor Morag, Wood Henry, Hutchins Gordon, Foster Joseph M, Oumie Assa, Spink Karen G, Brown Sarah R, Jones Marc, Kerr David, Handley Kelly, Gray Richard, Seymour Matthew, Quirke Philip

机构信息

Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, UK.

Histopathology and Molecular Pathology, St James University Hospital, Leeds, UK.

出版信息

J Pathol. 2016 Mar;238(4):562-70. doi: 10.1002/path.4679. Epub 2016 Jan 29.

DOI:10.1002/path.4679
PMID:26690310
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4785607/
Abstract

HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

摘要

人表皮生长因子受体2（HER2）的过表达/扩增与乳腺癌/胃癌中曲妥珠单抗的反应相关。在结直肠癌（CRC）中，一种推测的抗表皮生长因子受体（EGFR）耐药机制是通过HER2上调导致丝裂原活化蛋白激酶（MEK）-蛋白激酶B（AKT）途径异常激活。我们评估了II-III期和IV期CRC患者中HER2的扩增/过表达情况，并评估其与KRAS/BRAF以及预后的关系。病理材料取自QUASAR II-III期试验中的1914例患者以及IV期试验（FOCUS和PICCOLO）中的1342例患者。制作组织芯片用于HER2免疫组化检测。使用荧光原位杂交（FISH）和拷贝数变异评估HER2扩增情况。通过焦磷酸测序评估KRAS/BRAF突变状态。获取了FOCUS/PICCOLO试验的无进展生存期（PFS）和总生存期（OS）数据以及QUASAR试验的复发和死亡率数据；IV期肿瘤中有29/1342例（2.2%）、II-III期肿瘤中有25/1914例（1.3%）出现HER2蛋白过表达。在HER2过表达病例中，IV期肿瘤有27/28例（96.4%）、II-III期肿瘤有20/24例（83.3%）通过FISH检测显示HER2扩增；41/47例（87.2%）也显示拷贝数增加。HER2过表达在各阶段均与KRAS/BRAF野生型（WT）状态相关：IV期WT肿瘤中为5.2%，突变肿瘤中为1.0%（p<0.0001）；II-III期肿瘤中分别为2.1%和0.2%（p = 0.01）。HER2与OS或PFS无关。在II-III期，HER2过表达与5-氟尿嘧啶/亚叶酸（5FU/FA）反应之间无显著相关性。HER2过表达病例的复发比例较高，但差异不显著。HER2扩增/过表达可通过免疫组化识别，在II-III期CRC中发生率较低，在IV期升高，在KRAS/BRAF WT肿瘤中更高。HER2扩增的CRC患者中HER2靶向治疗的价值必须在临床试验中进行检验。© 2015作者。《病理学杂志》由John Wiley & Sons Ltd代表大不列颠及爱尔兰病理学会出版。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/e59436156d89/PATH-238-562-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/4de98c018fd2/PATH-238-562-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/754fcad845a9/PATH-238-562-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/3089fa9cbfe8/PATH-238-562-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/e59436156d89/PATH-238-562-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/4de98c018fd2/PATH-238-562-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/754fcad845a9/PATH-238-562-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/3089fa9cbfe8/PATH-238-562-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/680e/4785607/e59436156d89/PATH-238-562-g004.jpg

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