Akcakanat Argun, Sahin Aysegul, Shaye Alexandra N, Velasco Marco A, Meric-Bernstam Funda
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer. 2008 Jun;112(11):2352-8. doi: 10.1002/cncr.23456.
The Akt/mammalian target of the rapamycin (mTOR) signaling pathway represents a promising target for cancer therapy. The phosphorylation status of Akt and of mTOR's phosphorylation target eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is often used to assess the activity of Akt and mTOR signaling. The purpose of this study was to determine whether primary tumors differ from their metastasis in their expression of pAkt and p4E-BP1.
Primary breast tumors and their distant metastases surgically resected from the same patients were evaluated with immunohistochemical analysis (IHC) for pAkt (Ser473) and p4E-BP1 (Ser65). The agreement between the IHC results for the primary tumor and metastases was evaluated with Cohen kappa (kappa).
Most primary breast tumors and metastatic tumors expressed pAkt (76% of each). Of the 23 matched evaluable pairs, however, 11 (47.8%) had discordant IHC results (kappa -0.31; 95% confidence interval [CI], -0.49 to -0.13). Similarly, although most of the primary and metastatic tumors were positive for p4E-BP1 (75% and 74%), of the 23 matched evaluable pairs, 8 (47.8%) were discordant (kappa 0.10; 95% CI, -0.33-0.52).
In this series, most primary breast tumors and metastases expressed pAkt and p4E-BP1 by IHC. Concordance between IHC findings in primary tumors and metastases was poor, however. Further work is needed to determine whether this reflects true biological heterogeneity or poor reproducibility of IHC with phosphospecific antibodies, and to identify which biomarkers can be assessed most reproducibly in primary tumors to predict activity of Akt/mTOR signaling and sensitivity to pathway inhibitors.
Akt/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路是癌症治疗中一个很有前景的靶点。Akt的磷酸化状态以及mTOR的磷酸化靶点真核起始因子4E结合蛋白1（4E-BP1）的磷酸化状态常被用于评估Akt和mTOR信号通路的活性。本研究的目的是确定原发性肿瘤与其转移灶在pAkt和p4E-BP1表达上是否存在差异。
对同一患者手术切除的原发性乳腺肿瘤及其远处转移灶进行免疫组织化学分析（IHC），检测pAkt（Ser473）和p4E-BP1（Ser65）。采用Cohen卡方检验（kappa）评估原发性肿瘤和转移灶IHC结果之间的一致性。
大多数原发性乳腺肿瘤和转移瘤均表达pAkt（各占76%）。然而，在23对可评估的配对样本中，有11对（47.8%）的IHC结果不一致（kappa值为-0.31；95%置信区间[CI]，-0.49至-0.13）。同样，虽然大多数原发性和转移性肿瘤的p4E-BP1呈阳性（分别为75%和74%），但在23对可评估的配对样本中，有8对（47.8%）结果不一致（kappa值为0.10；95%CI，-0.33至0.52）。
在本研究系列中，大多数原发性乳腺肿瘤和转移灶通过IHC检测均表达pAkt和p4E-BP1。然而，原发性肿瘤和转移灶的IHC结果一致性较差。需要进一步研究以确定这是反映了真正的生物学异质性还是磷酸化特异性抗体IHC的可重复性差，并确定在原发性肿瘤中哪些生物标志物能够以最高的可重复性进行评估，以预测Akt/mTOR信号通路的活性以及对该通路抑制剂的敏感性。
