Fuentes Bayne H E, Suleiman R, Eiring R A, McGarrah P W, Thome S D, Graham R P, Garcia J J, Halfdanarson T R
Division of Medical Oncology, Mayo Clinic, Rochester, USA.
Division of Medical Oncology, Mayo Clinic, Rochester, USA.
ESMO Open. 2025 Jul 23;10(8):105515. doi: 10.1016/j.esmoop.2025.105515.
Cancer of unknown primary (CUP) remains a diagnostic and therapeutic challenge with limited treatment guidance. Caudal type homeobox 2 (CDX2), a transcription factor indicative of intestinal differentiation, may define a distinct subset of CUP with potential sensitivity to 5-fluorouracil (5-FU)-based chemotherapy. This study examines outcomes in patients with CDX2-positive CUP and the predictive value of CDX2 expression for response to 5-FU-based regimens.
We analyzed data from CDX2-positive CUP patients in the Mayo Clinic Cancer of Unknown Primary registry. All patients underwent comprehensive diagnostic evaluations and received first-line systemic therapy, categorized as 5-FU-based or non-5-FU-based. Primary endpoints were objective response rate (ORR) and clinical benefit rate; secondary endpoints included progression-free survival at first progression (PFS1) and overall survival. Logistic and Cox regression models were used to identify predictors of ORR and survival.
A total of 209 CDX2-positive CUP patients met inclusion criteria. The median age was 64 years (range 18-89 years), with 115 (55%) female patients. Adenocarcinoma was the predominant histology in 147 patients (74.7%), while only 39 (18.7%) exhibited the classical colorectal-like immunoprofile (CK7-negative/CK20-positive/CDX2-positive). Most patients (203, 97.1%) had multiple metastatic sites, and 98 (46.9%) received 5-FU-based chemotherapy regimens. 5-FU-Based treatment was associated with a significantly higher ORR compared with non-5-FU regimens [68 of 98 (69.4%) versus 53 of 111 (47.7%), P = 0.002], as well as higher clinical benefit rate [84 of 98 (85.7%) versus 80 of 111 (72.1%), P = 0.017]. Multivariable logistic regression identified 5-FU use as the only independent predictor of response (OR 2.28, 95% confidence interval 1.23-4.23, P = 0.009). Median overall survival was longer in the 5-FU group compared with non-5-FU (21.0 versus 14.0 months, P = 0.008), as was median PFS1 (15.2 versus 6.3 months, P < 0.001). Multivariable Cox regression confirmed 5-FU therapy as an independent prognostic factor for longer PFS1 (hazard ratio 0.50, 95% confidence interval 0.31-0.80, P = 0.004).
CDX2-positive CUP represents a distinct subgroup with favorable response to 5-FU-based therapy, supporting CDX2 as a predictive biomarker for treatment selection.
原发灶不明的癌症（CUP）仍然是一个诊断和治疗难题，治疗指导有限。尾型同源盒2（CDX2）是一种指示肠道分化的转录因子，可能定义了CUP的一个独特亚组，对基于5-氟尿嘧啶（5-FU）的化疗可能具有潜在敏感性。本研究探讨CDX2阳性CUP患者的预后以及CDX2表达对基于5-FU方案反应的预测价值。
我们分析了梅奥诊所原发灶不明癌症登记处中CDX2阳性CUP患者的数据。所有患者均接受了全面的诊断评估，并接受了一线全身治疗，分为基于5-FU的治疗或非基于5-FU的治疗。主要终点为客观缓解率（ORR）和临床获益率；次要终点包括首次进展时无进展生存期（PFS1）和总生存期。采用逻辑回归和Cox回归模型来确定ORR和生存的预测因素。
共有209例CDX2阳性CUP患者符合纳入标准。中位年龄为64岁（范围18 - 89岁），其中115例（55%）为女性患者。腺癌是147例患者（74.7%）的主要组织学类型，而只有39例（18.7%）表现出典型的结直肠样免疫表型（CK7阴性/CK20阳性/CDX2阳性）。大多数患者（203例，97.1%）有多个转移部位，98例（46.9%）接受了基于5-FU的化疗方案。与非5-FU方案相比，基于5-FU的治疗的ORR显著更高[98例中的68例（69.4%）对111例中的53例（47.7%），P = 0.002]，临床获益率也更高[98例中的84例（85.7%）对111例中的80例（72.1%），P = 0.017]。多变量逻辑回归确定使用5-FU是反应的唯一独立预测因素（OR 2.28，95%置信区间1.23 - 4.23，P = 0.009）。5-FU组的中位总生存期长于非5-FU组（21.0个月对14.0个月，P = 0.008），中位PFS1也是如此（15.2个月对6.3个月，P < 0.001）。多变量Cox回归证实5-FU治疗是PFS1更长的独立预后因素（风险比0.50，95%置信区间0.31 - 0.80，P = 0.004）。
CDX2阳性CUP代表一个对基于5-FU治疗反应良好的独特亚组，支持CDX2作为治疗选择的预测生物标志物。
