Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA; Hoag Family Cancer Institute, Newport Beach, CA.
Unito of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy.
Clin Colorectal Cancer. 2018 Sep;17(3):e471-e488. doi: 10.1016/j.clcc.2018.03.006. Epub 2018 Mar 14.
No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study.
Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database.
High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages.
ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.
目前尚无生物标志物可预测转移性结直肠癌患者接受抗血管生成治疗的获益。ACVRL1（激活素受体样蛋白 1）编码 ALK1，后者是转化生长因子-β受体家族的成员，可指导病理性血管生成。我们在 TRIBE 研究中检测了肿瘤内 ACVRL1 及其他血管生成途径相关基因的表达，以鉴定分子标志物。
在 503 例随机患者中，有 228 例有足够的组织进行分析。使用逆转录聚合酶链反应检测福尔马林固定石蜡包埋标本中 VEGF-A、VEGF-B、VEGF-C、VEGFR1、VEGFR2、ACVRL1、EphB4 和 EGFL7 的表达。采用最大 χ 方法确定与无进展生存期（PFS）、总生存期（OS）、缓解率、早期肿瘤退缩和反应深度相关的信使 RNA 水平。递归分区树用于确定复合预后生物标志物谱。使用 Oncomine 数据库进行了计算机模拟验证。
在接受 FOLFOXIRI（5-氟尿嘧啶、亚叶酸钙、奥沙利铂、伊立替康）联合贝伐珠单抗和 FOLFIRI（5-氟尿嘧啶、亚叶酸钙、伊立替康）联合贝伐珠单抗治疗的患者中，高 ACVRL1 表达与总生存获益相关（FOLFOXIRI-贝伐珠单抗：32.7 个月 vs. 13.5 个月，风险比 [HR]，0.38，P=0.023；FOLFIRI-贝伐珠单抗：35.1 个月 vs. 22.0 个月，HR，0.36，P=0.006），并延长了 PFS（FOLFOXIRI-贝伐珠单抗：11.7 个月 vs. 5.9 个月，多变量 HR，0.17；P=0.001）。单变量和多变量分析显示，在接受 FOLFOXIRI-贝伐珠单抗治疗的患者中，ACVRL1 是反应率、PFS 和 OS 的最强判别因素，在接受 FOLFIRI-贝伐珠单抗治疗的患者中，ACVRL1 是 OS 的最强判别因素。在递归分区分析中，ACVRL1 是接受 FOLFOXIRI-贝伐珠单抗治疗的转移性结直肠癌患者缓解率、PFS 和 OS 的最强判别因素，也是接受 FOLFIRI-贝伐珠单抗治疗的患者 OS 的最强判别因素。计算机模拟验证显示，在所有结直肠癌分期中，ACVRL1 表达与疾病复发和 1 年生存率之间存在显著关联（P<0.05）。
ACVRL1 表达可作为接受化疗和贝伐珠单抗治疗的转移性结直肠癌患者的预后生物标志物，值得进一步在前瞻性研究中进行评估。
