Trock B J, Leonessa F, Clarke R
Department of Biomathematics and Biostatistics, and Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
J Natl Cancer Inst. 1997 Jul 2;89(13):917-31. doi: 10.1093/jnci/89.13.917.
P-glycoprotein (gp170; encoded by the MDR1 gene [also known as PGY1]) is a membrane protein capable of exporting a variety of anticancer drugs from cells. MDR1/gp170 expression has been studied in breast cancer, but the prevalence of this expression and its role in breast tumor drug resistance are unclear.
We conducted a critical review and meta-analysis of studies examining MDR1/gp170 expression in breast cancer to estimate the likely prevalence and clinical relevance of this expression. We also explored reasons for differences in the findings from individual studies.
Published papers on MDR1/gp170 expression in breast cancer were identified by searching several literature databases and reviewing the bibliographies of identified papers. Variability across the studies in the proportion of tumors expressing MDR1/gp170 was assessed by use of chi-squared tests of homogeneity, weighted means, and weighted linear regression. Pooled relative risks (RRs) for the association between the induction of MDR1/gp170 expression and prior chemotherapy and associations between MDR1/gp170 expression and several clinical outcomes were estimated by use of Mantel-Haenszel methods. Heterogeneity among the pooled RRs was explored by use of chi-squared tests. Reported P values are two-sided.
Thirty-one studies were identified and evaluated. The proportion of breast tumors expressing MDR1/gp170 in all of the studies was 41.2%, but there was substantial heterogeneity in the values across individual studies (P<.0001). Regression analyses demonstrated that a considerable portion of the observed heterogeneity was a consequence of the change, over time, from RNA hybridization-based assays to immunohistochemistry-based assays of MDR1/gp170 expression. Measuring MDR1/gp170 expression before versus after chemotherapy and use of cytotoxic drugs that are not substrates for gp170 also contributed to the heterogeneity. Treatment with chemotherapeutic drugs or hormonal agents was associated with an increase in the proportion of tumors expressing MDR1/gp170 (RR = 1.77; 95% confidence interval [CI] = 1.46-2.15). Patients with tumors expressing MDR1/gp170 were three times more likely to fail to respond to chemotherapy than patients whose tumors were MDR1/gp170 negative (RR = 3.21; 95% CI = 2.28-4.51); this RR increased to 4.19 (95% CI = 2.71-6.47) when considering only patients whose tumor expression of MDR1/gp170 was measured after chemotherapy. MDR1/gp170 expression was not associated with lymph node metastases, estrogen receptor status, tumor size, tumor grade, or tumor histology.
MDR1/gp170 expression in breast tumors is associated with treatment and with a poor response to chemotherapy. The data are consistent with a contributory role for MDR1/gp170 in the multidrug resistance in some breast tumors.
P-糖蛋白（gp170；由MDR1基因[也称为PGY1]编码）是一种能够将多种抗癌药物从细胞中输出的膜蛋白。已对乳腺癌中的MDR1/gp170表达进行了研究，但这种表达的普遍性及其在乳腺肿瘤耐药性中的作用尚不清楚。
我们对研究乳腺癌中MDR1/gp170表达的研究进行了批判性综述和荟萃分析，以估计这种表达可能的普遍性和临床相关性。我们还探讨了个体研究结果存在差异的原因。
通过检索多个文献数据库并查阅已识别论文的参考文献，确定了关于乳腺癌中MDR1/gp170表达的已发表论文。使用同质性卡方检验、加权均值和加权线性回归评估各研究中表达MDR1/gp170的肿瘤比例的变异性。使用Mantel-Haenszel方法估计MDR1/gp170表达诱导与既往化疗之间关联以及MDR1/gp170表达与几种临床结局之间关联的合并相对风险（RR）。使用卡方检验探讨合并RR之间的异质性。报告的P值为双侧。
识别并评估了31项研究。所有研究中表达MDR1/gp170的乳腺肿瘤比例为41.2%，但各研究中的值存在显著异质性（P<0.0001）。回归分析表明，观察到的相当一部分异质性是由于随着时间推移，从基于RNA杂交的检测方法转变为基于免疫组织化学的MDR1/gp170表达检测方法所致。化疗前后测量MDR1/gp170表达以及使用不是gp170底物的细胞毒性药物也导致了异质性。化疗药物或激素药物治疗与表达MDR1/gp170的肿瘤比例增加相关（RR = 1.77；95%置信区间[CI] = 1.46 - 2.15）。与肿瘤为MDR1/gp170阴性的患者相比，肿瘤表达MDR1/gp170的患者对化疗无反应的可能性高出三倍（RR = 3.21；95% CI = 2.28 - 4.51）；仅考虑化疗后测量肿瘤MDR1/gp170表达的患者时，该RR增至4.19（95% CI = 2.71 - 6.47）。MDR1/gp170表达与淋巴结转移、雌激素受体状态、肿瘤大小、肿瘤分级或肿瘤组织学无关。
乳腺肿瘤中的MDR1/gp170表达与治疗以及化疗反应不佳相关。数据表明MDR1/gp170在某些乳腺肿瘤的多药耐药中起作用。
