University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland.
Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland.
BMC Cancer. 2022 Apr 9;22(1):376. doi: 10.1186/s12885-022-09374-x.
Ovarian cancer (OC) is the fifth most common malignant female cancer with a high mortality, mainly because of aggressive high-grade serous carcinomas (HGSOC), but also due to absence of specific early symptoms and effective detection strategies. The CXCL12-CXCR4 axis is considered to have a prognostic impact and to serve as potential therapeutic target. Therefore we investigated the role of pCXCR4 and CXCR4 expression of the tumor cells and of tumor infiltrating immune cells (TIC) in high-grade serous OC and their association with the recurrence-free (RFS) and overall survival (OS).
A tissue microarray of 47 primary high grade ovarian serous carcinomas and their recurrences was stained with primary antibodies directed against CXCR4 and pCXCR4. Beside the evaluation of the absolute tumor as well as TIC expression in primary and recurrent cancer biopsies the corresponding ratios for pCXCR4 and CXCR4 were generated and analyzed. The clinical endpoints were response to chemotherapy, OS as well as RFS.
Patients with a high pCXCR4/CXCR4 TIC ratio in primary cancer biopsies showed a significant longer RFS during the first two years (p = 0.025). However, this effect was lost in the long-term analysis including a follow-up period of 5 years (p = 0.128). Interestingly, the Multivariate Cox regression analysis showed that a high pCXCR4/CXCR4 TIC ratio in primary cancer independently predicts longer RFS (HR 0.33; 95CI 0.13 - 0.81; p = 0.015). Furthermore a high dichotomized distribution of CXCR4 positive tumor expression in recurrent cancer biopsies showed a significantly longer 6-month RFS rate (p = 0.018) in comparison to patients with low CXCR4 positive tumor expression. However, this effect was not independent of known risk factors in a Multivariate Cox regression (HR 0.57; 95CI 0.24 - 1.33; p = 0.193).
To the best of our knowledge we show for the first time that a high pCXCR4/CXCR4 TIC ratio in primary HGSOC biopsies is indicative for better RFS and response to chemotherapy.
• We observed a significant association between high pCXCR4/CXCR4 TIC ratio and better RFS in primary cancer biopsies, especially during the early postoperative follow-up and independent of known risk factors for recurrence. • High CXCR4 tumor expression in recurrent HGSOC biopsies might be indicative for sensitivity to chemotherapy. We found evidence that at the beginning of the disease (early follow-up) the role of the immune response seems to be the most crucial factor for progression. On the other hand in recurrent/progressive disease the biology of the tumor itself becomes more important for prognosis. • We explored for the first time the predictive and prognostic role of pCXCR4/CXCR4 TIC ratio in high-grade serous ovarian cancer.
卵巢癌（OC）是第五大常见的女性恶性肿瘤，死亡率较高，主要是由于侵袭性高级别浆液性癌（HGSOC），但也由于缺乏特异性的早期症状和有效的检测策略。CXCL12-CXCR4 轴被认为具有预后影响，并可作为潜在的治疗靶点。因此，我们研究了 pCXCR4 和肿瘤细胞中 CXCR4 的表达在高级别浆液性 OC 中的作用及其与无复发生存（RFS）和总生存（OS）的关系。
使用针对 CXCR4 和 pCXCR4 的初级抗体对 47 例原发性高级别卵巢浆液性癌及其复发病灶的组织微阵列进行染色。除了评估原发性和复发性癌症活检中肿瘤的绝对表达以及肿瘤浸润免疫细胞（TIC）的表达外，还生成并分析了 pCXCR4 和 CXCR4 的相应比值。临床终点是对化疗的反应、OS 以及 RFS。
原发性癌症活检中 pCXCR4/CXCR4 TIC 比值较高的患者在前两年的 RFS 显著延长（p = 0.025）。然而，在包括 5 年随访期的长期分析中，这种效果消失（p = 0.128）。有趣的是，多变量 Cox 回归分析表明，原发性癌症中 pCXCR4/CXCR4 TIC 比值较高独立预测 RFS 延长（HR 0.33；95CI 0.13 - 0.81；p = 0.015）。此外，复发性癌症活检中 CXCR4 阳性肿瘤表达的高二分类分布显示，6 个月的 RFS 率显著延长（p = 0.018），与 CXCR4 阳性肿瘤表达较低的患者相比。然而，在多变量 Cox 回归中，这一效应并非独立于已知的复发风险因素（HR 0.57；95CI 0.24 - 1.33；p = 0.193）。
据我们所知，我们首次表明，原发性 HGSOC 活检中 pCXCR4/CXCR4 TIC 比值较高与 RFS 较好和对化疗的反应有关。
• 我们观察到，原发性癌症活检中 pCXCR4/CXCR4 TIC 比值高与 RFS 之间存在显著相关性，尤其是在术后早期随访期间，并且独立于复发的已知风险因素。• 在复发性 HGSOC 活检中，高 CXCR4 肿瘤表达可能预示着对化疗的敏感性。我们有证据表明，在疾病的早期（早期随访），免疫反应的作用似乎是疾病进展的最关键因素。另一方面，在复发性/进展性疾病中，肿瘤本身的生物学对预后变得更为重要。• 我们首次探讨了 pCXCR4/CXCR4 TIC 比值在高级别浆液性卵巢癌中的预测和预后作用。
