Department of Abdominal Oncology, SSD-Innovative Therapies for Abdominal Metastases.
Department of Molecular Immunology.
Appl Immunohistochem Mol Morphol. 2020 Nov/Dec;28(10):755-760. doi: 10.1097/PAI.0000000000000828.
Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. About 30% of patients present with metastatic disease involving predominantly the liver and a similar percentage will develop distant metastases later after removal of the primary tumor. In metastatic CRC, chemotherapies and biological drugs have prolonged survival for up to 30 months. However, there is a great need for biomarkers predictive of response and prognosis to optimize treatments. CXC chemokine receptor 4 (CXCR4) is a chemokine receptor; it binds to CXCL12 and plays a central role in colon cancer cells' growth and dissemination.
CXCR4 was evaluated in CRC primary tissues by immunohistochemistry. Formalin-fixed, paraffin-embedded 4-μm tissue sections were immunostained using a biotin-streptavidin-peroxidase method and categorized into 2 semiquantitative classes: (i) absence of staining, ≤50% positive cells (negative/low) and (ii) >50% positive cells (high). Associations between clinic-pathologic variables and CXCR4 expression were evaluated using the χ test. The Kaplan-Meier product-limit method was applied to graph overall survival (OS). OS was defined as the time elapsed from diagnosis to death from any cause. Univariate analysis was carried out using the log-rank test. Cox proportional hazards regression was used to analyze the effect of several risk factors on OS.
Seventy-eight primary adenocarcinomas were analyzed; 26 were categorized as negative/low and 52 as high. Age, sex, performance status, site of metastases, KRAS mutational status, type of first-line therapy, and a number of therapy lines did not correlate with CXCR4 expression. Although not significant (P=0.0533), high CXCR4 expression was more frequently localized on the right side of the colon. Significant correlations were detected with grading (P=0.0041) and response to first-line anti-epidermal growth factor receptors agents (P<0.0001), bevacizumab (P=0.0029), and chemotherapy alone (P=0.0260). At a median follow-up of 53 months, 77 deaths have been registered. Grading [hazard ratio (HR): 1.42; confidence interval (CI): 0.89-2.28; P<0.0001], KRAS mutational status (HR: 1.73; CI: 1.03-290; P=0.0133), response to first-line chemotherapy (HR: 3.39; CI: 2.10-5.48; P<0.0001), and CXCR4 expression (HR: 3.18; CI: 2.01-5.02; P<0.0001) showed prognostic power at univariate and multivariate analyses.
In the present report, we show that CXCR4 expression on the primary tumor is an independent prognostic factor and correlates with response to first-line chemotherapy in metastatic CRC patients.
结直肠癌（CRC）是全球癌症相关死亡的第三大主要原因。约 30%的患者存在主要累及肝脏的转移性疾病，类似比例的患者在原发性肿瘤切除后会发生远处转移。在转移性 CRC 中，化疗和生物药物可将生存期延长至 30 个月。然而，非常需要有预测反应和预后的生物标志物来优化治疗。CXC 趋化因子受体 4（CXCR4）是一种趋化因子受体；它与 CXCL12 结合，在结肠癌细胞的生长和扩散中发挥核心作用。
通过免疫组织化学评估 CRC 原发性组织中的 CXCR4。使用生物素-链霉亲和素-过氧化物酶方法对福尔马林固定、石蜡包埋的 4μm 组织切片进行免疫染色，并分为 2 个半定量等级：（i）无染色，≤50%阳性细胞（阴性/低）和（ii）>50%阳性细胞（高）。使用 χ 检验评估临床病理变量与 CXCR4 表达之间的关联。Kaplan-Meier 乘积限法用于绘制总生存期（OS）图。OS 定义为从诊断到任何原因死亡的时间。使用对数秩检验进行单因素分析。Cox 比例风险回归用于分析多个风险因素对 OS 的影响。
分析了 78 例原发性腺癌；26 例被归类为阴性/低，52 例为高。年龄、性别、表现状态、转移部位、KRAS 突变状态、一线治疗类型以及治疗线数与 CXCR4 表达无关。虽然没有统计学意义（P=0.0533），但高 CXCR4 表达更常发生在结肠右侧。与分级（P=0.0041）和对一线抗表皮生长因子受体药物的反应（P<0.0001）、贝伐珠单抗（P=0.0029）和单独化疗（P=0.0260）显著相关。在中位随访 53 个月时，已登记 77 例死亡。分级[风险比（HR）：1.42；置信区间（CI）：0.89-2.28；P<0.0001]、KRAS 突变状态（HR：1.73；CI：1.03-290；P=0.0133）、对一线化疗的反应（HR：3.39；CI：2.10-5.48；P<0.0001）和 CXCR4 表达（HR：3.18；CI：2.01-5.02；P<0.0001）在单因素和多因素分析中均显示出预后能力。
在本报告中，我们表明原发性肿瘤上的 CXCR4 表达是独立的预后因素，并与转移性 CRC 患者一线化疗的反应相关。
