Paterson M C, Dietrich K D, Danyluk J, Paterson A H, Lees A W, Jamil N, Hanson J, Jenkins H, Krause B E, McBlain W A
Breast Unit, Cross Cancer Institute, Edmonton, Alberta, Canada.
Cancer Res. 1991 Jan 15;51(2):556-67.
Drawing upon the comprehensive population-based Northern Alberta Breast Cancer Registry containing 704 patients with histologically negative axillary lymph nodes who have been followed for 5-16 years, we have undertaken a retrospective case-control study to evaluate the utility of genomic amplification of specific protooncogenes [c-erbB-2 (nee HER-2/neu), c-erbA, c-myc, int-2, and hst-1] as predictive indicators of clinical outcome in node-negative disease. To this end, 115 women with node-negative breast cancer who had recurred at any time up to 16 years posttreatment (cases) were matched pairwise for appropriate clinicopathological variables (size of primary tumor, menopausal state, estrogen receptor status, anniversary year of treatment, and patient age) with a second group of 115 women (controls) selected from a cohort of 502 node-negative patients who had not relapsed during long-term follow-up. Tumor DNA extracted from archival formalin-fixed, paraffin-embedded tissue blocks were analyzed for protooncogene copy number by slot-blot hybridization. Taking a gene copy number of 3 as the cutoff, 27 of the 230 tumor samples examined contained from 3- to 22-fold elevation in c-erbB-2 genomic equivalents. Twenty-one of the 27 tumors amplified for c-erbB-2 were derived from cases and 6 from controls, signifying that 18% of the node-negative patients who had relapsed harbored excessive copies of the protooncogene in their malignant tissue compared to only 5% for the patients who had remained in remission. Accordingly, the occurrence of amplification of c-erbB-2 proved to be a statistically significant predictor of poor prognosis, especially disease-free interval (P = 0.006). Moreover, this genetic alteration appeared to be independent of and to have greater predictive power than most commonly used prognostic factors. Our findings also indicated that as a clinical test, measurement of c-erbB-2 amplification suffers from low sensitivity; however, when greater than 6 gene copies are present, the test has a positive predictive value for recurrence of 70%. Concurrent analysis of tumor DNA blots with probes for the other four protooncogenes examined revealed that their amplification, which others have reported to arise often, especially in node-positive disease, was seldom found even in our high-risk case group (2-3%). In short, our data strongly suggest that amplification of c-erbB-2 may contribute to the pathogenesis of some forms of node-negative breast cancer and thus may serve as a useful genetic marker to identify a subset of high-risk patients.
利用基于人群的综合性艾伯塔省北部乳腺癌登记处的数据，该登记处包含704例组织学检查腋窝淋巴结阴性且已随访5至16年的患者，我们进行了一项回顾性病例对照研究，以评估特定原癌基因（c-erbB-2（原称HER-2/neu）、c-erbA、c-myc、int-2和hst-1）的基因组扩增作为淋巴结阴性疾病临床结局预测指标的效用。为此，将115例治疗后16年内任何时间复发的淋巴结阴性乳腺癌女性（病例组）与另一组115例女性（对照组）进行配对，使其在适当的临床病理变量（原发肿瘤大小、绝经状态、雌激素受体状态、治疗周年和患者年龄）方面相匹配，对照组从502例长期随访未复发的淋巴结阴性患者队列中选取。从存档的福尔马林固定、石蜡包埋组织块中提取肿瘤DNA，通过狭缝印迹杂交分析原癌基因拷贝数。以基因拷贝数3为临界值，在检测的230个肿瘤样本中，有27个样本的c-erbB-2基因组当量升高了3至22倍。27个c-erbB-2基因扩增的肿瘤中，21个来自病例组，6个来自对照组，这表明复发的淋巴结阴性患者中有18%在其恶性组织中携带原癌基因的过量拷贝，而仍处于缓解期的患者这一比例仅为5%。因此，c-erbB-2基因扩增的发生被证明是预后不良的统计学显著预测指标，尤其是无病生存期（P = 0.006）。此外，这种基因改变似乎独立于大多数常用的预后因素，且具有更强的预测能力。我们的研究结果还表明，作为一项临床检测，c-erbB-2基因扩增检测的敏感性较低；然而，当存在超过6个基因拷贝时，该检测对复发的阳性预测值为70%。用检测其他四个原癌基因的探针同时分析肿瘤DNA印迹，结果显示，其他人报道的这些基因的扩增情况经常出现，尤其是在淋巴结阳性疾病中，但即使在我们的高危病例组中也很少发现（2 - 3%）。简而言之，我们的数据强烈表明，c-erbB-2基因扩增可能在某些形式的淋巴结阴性乳腺癌发病机制中起作用，因此可作为识别高危患者亚组的有用遗传标志物。
