Li Yilin, Peng Zhi, Zhang Xiaotian, Gong Jifang, Shen Lin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
Zhonghua Wei Chang Wai Ke Za Zhi. 2017 Nov 25;20(11):1293-1299.
To examine the correlation between serum human epithelial growth factor receptor 2 extracellular domain (HER2 ECD) and circulating tumor cells (CTC), as well as the dynamic variation of HER2 ECD and its correlation to the therapeutic efficacy.
Fifty-three advanced gastric cancer (AGC) patients who treated in Peking University Cancer Hospital and ever enrolled into CTC study (ClinicalTrial gov. ID: NCT01625702) were retrospectively included in this study.
the patients were histologically confirmed as locally advanced or recurrent and/or metastatic adencarcinoma; they received two or more cycles of fluorouracil-based chemotherapy or combination targeted therapy; serum CTC was counted before and after therapy; the clinical response was evaluated every 2 cycles of treatment by the presence of at least one measurable lesion according to RECIST version 1.1 criteria. This study was approved by Ethics Committee of Peking University Cancer Hospital, and informed consents were signed by patients. The sera before and after two cycles of treatment were collected for CTC enumeration and HER2 ECD detection, in which the levels of HER2 ECD were measured by chemiluminescence immunoassays method. The positive threshold value of HER2 ECD and CTC number were ≥15 μg/L and ≥3 CTCs/7.5 ml respectively. The progression-free survival (PFS) and overall survival (OS) were compared among different groups using Log-rank tests.
In 53 enrolled patients, 39 were histologically identified as negative HER2, 9 as positive HER2 and another 5 cases were unknown. All the patients received fluorouracil-based chemotherapy, and 9 positive HER2 patients received combined anti-HER2 targeted therapy. Before therapy, the median HER2 ECD concentration of 53 cases was 10.45 (8.0 to 83.2) μg/L. Seven patients exhibited positive HER2 ECD levels, in whom 4 were histologically HER2 positive, but 3 were histologically HER2 negative. The median CTC number of 53 cases was 2 (0 to 668) CTCs/7.5 ml, and the positive rate of CTC was 47.2%(25/53). Following 2 cycles of therapy, a total of 10 histologically HER2 negative patients exhibited positive HER2 ECD levels, in whom 2 also possessed positive HER2 ECD levels, 83.3 μg/L and 46.9 μg/L before therapy, and 22.4 μg/L and 20.4 μg/L after therapy respectively, whereas another 8 patients (10.3 to 14.5 μg/L before therapy) acquired the elevated expression of HER2 ECD following therapy (15.1 to 19.5 μg/L). It seems that the increased level of HER2 ECD after therapy was, though not statistically significant, correlated to low number of CTCs. In histologically HER2 negative patients, pretherapeutic HER2 ECD level (positive vs. negative) was not significantly correlated to PFS (7.6 months vs. 4.4 months, P=0.328) and OS (13.6 months vs. 10.9 months, P=0.679). However, in histologically HER2 positive patients, patients with positive HER2 ECD level before therapy exhibited longer PFS (10.7 months vs. 4.2 months, P=0.025) and OS (16.5 months vs. 8.9 months, P=0.015) compared to those with negative HER2 ECD level. Additionally, CTC number was significantly correlated to prognosis in histologically HER2 negative patients. Patients with positive pretherapeutic CTC number showed longer PFS (5.3 months vs. 3.3 months, P=0.049) and OS (14.3 months vs. 7.6 months, P=0.001) as well. While in histologically HER2 positive patients, CTC number was not obviously correlated to the PFS and OS. In above 8 negative HER2 patients acquiring elevated expression of HER2 ECD following therapy, the increased HER2 ECD level was not correlated to PFS and OS (all P>0.05). In 9 histologically HER2 positive patients, 4 patients who exhibited decreased HER2 ECD level and reduced or constant CTC number had longer PFS (7.5 to 15.3 months) and OS (11.0 to 26.3 months) compared with those 2 patients who suffered from acquired HER2 ECD level following therapy (PFS 3.0 to 4.8 months and OS 7.3 to 8.6 months).
In histologically HER2 positive patients, increased pretherapeutic HER2 ECD level predicts better prognosis. The acquired elevated HER2 ECD level following therapy is correlated to inefficient therapeutic response. The acquirement of elevated HER2 ECD level can also be found in histologically HER2 negative patients, which may be correlated to the corresponding variation of CTC number.
探讨血清人表皮生长因子受体2细胞外结构域（HER2 ECD）与循环肿瘤细胞（CTC）之间的相关性，以及HER2 ECD的动态变化及其与治疗疗效的相关性。
回顾性纳入53例在北京大学肿瘤医院接受治疗且曾参与CTC研究（ClinicalTrial gov. ID: NCT01625702）的晚期胃癌（AGC）患者。
患者经组织学确诊为局部晚期或复发和/或转移性腺癌；接受过两个或更多周期的氟尿嘧啶类化疗或联合靶向治疗；治疗前后计数血清CTC；根据RECIST 1.1标准，每2个周期治疗通过至少一个可测量病灶评估临床反应。本研究经北京大学肿瘤医院伦理委员会批准，患者签署知情同意书。收集两个周期治疗前后的血清用于CTC计数和HER2 ECD检测，其中HER2 ECD水平采用化学发光免疫分析法测定。HER2 ECD的阳性阈值和CTC数量分别为≥15 μg/L和≥3个CTC/7.5 ml。采用Log-rank检验比较不同组的无进展生存期（PFS）和总生存期（OS）。
53例纳入患者中，39例组织学鉴定为HER2阴性，9例为HER2阳性，另外5例未知。所有患者均接受氟尿嘧啶类化疗，9例HER2阳性患者接受联合抗HER2靶向治疗。治疗前，53例患者的HER2 ECD浓度中位数为10.45（8.0至83.2）μg/L。7例患者HER2 ECD水平呈阳性，其中4例组织学HER2阳性，但3例组织学HER2阴性。53例患者的CTC中位数为2（0至668）个CTC/7.5 ml，CTC阳性率为47.2%（25/53）。经过2个周期治疗后，共有10例组织学HER2阴性患者HER2 ECD水平呈阳性，其中2例治疗前HER2 ECD水平也呈阳性，分别为83.3 μg/L和46.9 μg/L，治疗后分别为22.4 μg/L和20.4 μg/L，而另外8例患者（治疗前10.3至14.5 μg/L）治疗后HER2 ECD表达升高（15.1至19.5 μg/L）。治疗后HER2 ECD水平升高似乎与CTC数量少相关，尽管无统计学意义。在组织学HER2阴性患者中，治疗前HER2 ECD水平（阳性与阴性）与PFS（7.6个月对4.4个月，P = 0.328）和OS（13.6个月对10.9个月，P = 0.679）无显著相关性。然而，在组织学HER2阳性患者中，治疗前HER2 ECD水平呈阳性的患者与HER2 ECD水平呈阴性的患者相比，PFS更长（10.7个月对4.2个月，P = 0.025），OS更长（16.5个月对8.9个月，P = 0.015）。此外，在组织学HER2阴性患者中，CTC数量与预后显著相关。治疗前CTC数量呈阳性的患者PFS更长（5.3个月对3.3个月，P = 0.049），OS也更长（14.3个月对7.6个月，P = 0.001）。而在组织学HER2阳性患者中，CTC数量与PFS和OS无明显相关性。在上述8例治疗后HER2 ECD表达升高的HER2阴性患者中，HER2 ECD水平升高与PFS和OS均无相关性（均P>0.05）。在9例组织学HER2阳性患者中，4例HER2 ECD水平降低且CTC数量减少或稳定的患者与2例治疗后HER2 ECD水平升高的患者相比，PFS更长（7.5至15.3个月），OS更长（11.0至26.3个月）（PFS 3.0至4.8个月，OS 7.3至8.6个月）。
在组织学HER2阳性患者中，治疗前HER2 ECD水平升高预示较好预后。治疗后获得性HER2 ECD水平升高与治疗反应不佳相关。在组织学HER2阴性患者中也可发现HER2 ECD水平升高，这可能与CTC数量的相应变化有关。
