Doll Corinne M, Moughan Jennifer, Klimowicz Alexander, Ho Clement K, Kornaga Elizabeth N, Lees-Miller Susan P, Ajani Jaffer A, Crane Christopher H, Kachnic Lisa A, Okawara Gordon S, Berk Lawrence B, Roof Kevin S, Becker Mark J, Grisell David L, Ellis Robert J, Sperduto Paul W, Marsa Gerald W, Guha Chandan, Magliocco Anthony M
Tom Baker Cancer Centre, Calgary, Alberta, Canada.
NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania.
Int J Radiat Oncol Biol Phys. 2017 Mar 1;97(3):554-562. doi: 10.1016/j.ijrobp.2016.11.021. Epub 2016 Nov 23.
To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome.
EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFR) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored.
A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFR ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFR ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution.
High Ki67ratio in EGFR is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.
在参与NRG肿瘤学RTOG 9811的肛门癌患者治疗前肿瘤活检中测量表皮生长因子受体（EGFR）和Ki67蛋白的共表达情况。NRG肿瘤学RTOG 9811是一项III期试验，比较5-氟尿嘧啶/丝裂霉素-C/放射治疗（A组）与5-氟尿嘧啶/顺铂/放射治疗（B组），并将表达情况与临床结果相关联。
使用荧光免疫组织化学和自动定量图像分析构建组织微阵列后，测量EGFR和Ki67的共表达情况。分析每个肿瘤核心中EGFR高表达区域与低表达区域内的Ki67评分（EGFR中的Ki67比率）的中位数、四分位数，并将其作为连续变量进行分析。探讨肿瘤标志物与临床终点（总生存期和无病生存期、局部区域和结肠造口失败以及远处转移）之间的关联。
共分析了来自NRG肿瘤学RTOG 9811的282例治疗前肿瘤。在评估的标本中，183例（65%，A组89例；B组94例）符合条件且可进行分析。可分析和不可分析的患者病例在基线特征或结果方面无显著差异。中位随访时间为6.0年。多因素分析显示，在调整性别后，EGFR中Ki67比率≥中位数的患者总生存期较差（风险比2.41，95%置信区间1.38 - 4.19，P = 0.0019）。在调整N分期和最大肿瘤尺寸后，EGFR中Ki67比率≥中位数的患者无病失败风险较高（风险比1.85，95%置信区间1.18 - 2.92，P = 0.0078）。对一个独立的肛门癌患者队列进行了技术验证，结果显示生物标志物评分分布非常相似。
在NRG肿瘤学RTOG 9811接受放化疗的这部分肛门癌患者中，EGFR中高Ki67比率与较差的临床结果相关。需要在临床试验中进行评估，以确定具有这些肿瘤特征的患者是否可能特别受益于EGFR靶向治疗药物。
