Background: 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. Materials and Methods: 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 χ2 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. Results: 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. Conclusion: 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.

中文翻译：

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CXC 趋化因子受体 4 在转移性结直肠癌患者中的预后和预测作用

背景：结直肠癌 (CRC) 是全球癌症相关死亡的第三大原因。大约 30% 的患者出现主要累及肝脏的转移性疾病，并且有相似比例的患者在切除原发肿瘤后会发生远处转移。在转移性结直肠癌中，化疗和生物药物可延长生存期长达 30 个月。然而，非常需要预测反应和预后的生物标志物以优化治疗。CXC 趋化因子受体 4 (CXCR4) 是一种趋化因子受体；它与 CXCL12 结合并在结肠癌细胞的生长和传播中发挥核心作用。材料和方法：通过免疫组织化学在 CRC 原发组织中评估 CXCR4。福尔马林固定，使用生物素-链霉亲和素-过氧化物酶方法对石蜡包埋的 4 μm 组织切片进行免疫染色，并分为 2 个半定量类别：(i) 无染色，≤50% 阳性细胞（阴性/低）和 (ii)> 50% 阳性细胞（高）。使用 χ2 检验评估临床病理变量与 CXCR4 表达之间的关联。Kaplan-Meier 乘积极限方法用于绘制总生存期 (OS) 图表。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变量分析。Cox 比例风险回归用于分析几个风险因素对 OS 的影响。结果：分析了78例原发性腺癌；26 被归类为负面/低，52 被归类为高。年龄、性别、体能状态、转移部位、KRAS 突变状态、一线治疗类型和许多治疗线与 CXCR4 表达无关。虽然不显着（P = 0.0533），但高 CXCR4 表达更频繁地位于结肠右侧。检测到分级（P = 0.0041）和对一线抗表皮生长因子受体药物（P <0.0001）、贝伐单抗（P = 0.0029）和单独化疗（P = 0.0260）的反应显着相关。中位随访时间为 53 个月，已有 77 人死亡。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）在单变量和多变量分析中显示出预测能力。结论：在本报告中，我们表明原发肿瘤上的 CXCR4 表达是一个独立的预后因素，并且与转移性 CRC 患者对一线化疗的反应相关。