Dittadi R, Biganzoli E, Boracchi P, Salbe C, Mione R, Gatti C, Gion M
Center for the Study of Biological Markers of Malignancy, Ospedale Civile, Venezia, Italy.
Int J Biol Markers. 1998 Jan-Mar;13(1):30-41.
In spite of the complexity of the biological basis of the hormonal regulation of breast cancer, clinical studies tend to simplify the information by mainly categorizing continuous variables related to hormonal status and not considering the interactions between variables. The present study was planned to examine the presence of an interaction between cathepsin D (Cath-D) and pS2 in patients treated with adjuvant tamoxifen in a homogeneous subset of node-positive postmenopausal patients and to evaluate the contribution of the interaction to the predictive ability of the model. Steroid receptors (ER and PgR) were measured in cytosol using the dextran-coated charcoal method, while Cath-D and pS2 were determined using commercially available immunoradiometric assays. The prognostic role of each variable and their joint effect were investigated using a Cox regression model. Biological variables were analyzed as continuous and when their prognostic relationship did not seem linear, a restricted cubic spline regression smoothing approach was adopted. The logarithm of hazard showed a linear relationship with the log(ER), while it i) remained almost constant up to about 20 fmol/mg and subsequently decreased for PgR; ii) was almost constant up to about 50 pmol/mg and subsequently decreased for Cath-D; iii) decreased for increasing log(value) up to about 33 ng/mg and subsequently increased for pS2. In the multivariate analysis both PgR and the interaction between pS2 and Cath-D retained a significant prognostic role. For low values of pS2, the prognosis worsened with the increase in Cath-D levels and this relationship reversed for high values of pS2. From the results of the present study we can conclude that i) a significant interaction between Cath-D and pS2 was found in this case series; ii) the prognostic relationship should not be underestimated in clinical decision making; iii) a predictive score obtained considering the contribution of PgR, pS2 and Cath-D could be useful for clinical use.
尽管乳腺癌激素调节的生物学基础十分复杂，但临床研究往往通过主要对与激素状态相关的连续变量进行分类，而不考虑变量之间的相互作用来简化信息。本研究旨在检查在接受辅助他莫昔芬治疗的淋巴结阳性绝经后患者的同质亚组中组织蛋白酶D（Cath-D）和pS2之间是否存在相互作用，并评估这种相互作用对模型预测能力的贡献。使用葡聚糖包被活性炭法在细胞质中测量类固醇受体（ER和PgR），而使用市售免疫放射分析法定量Cath-D和pS2。使用Cox回归模型研究每个变量的预后作用及其联合效应。将生物学变量作为连续变量进行分析，当它们的预后关系似乎不是线性时，采用受限立方样条回归平滑方法。风险对数与log(ER)呈线性关系，而对于PgR，它在i）高达约20 fmol/mg时几乎保持恒定，随后下降；对于Cath-D，它在ii）高达约50 pmol/mg时几乎保持恒定，随后下降；对于pS2，它在iii）log(值)增加至约33 ng/mg之前下降，随后增加。在多变量分析中，PgR以及pS2和Cath-D之间的相互作用均保留了显著的预后作用。对于低水平的pS2，随着Cath-D水平的升高，预后恶化，而对于高水平的pS2，这种关系则相反。从本研究结果我们可以得出结论：i）在该病例系列中发现Cath-D和pS2之间存在显著相互作用；ii）在临床决策中不应低估预后关系；iii）考虑PgR、pS2和Cath-D的贡献所获得的预测评分可能对临床有用。
