Allred D C, Clark G M, Tandon A K, Molina R, Tormey D C, Osborne C K, Gilchrist K W, Mansour E G, Abeloff M, Eudey L
Department of Pathology, University of Texas Health Science Center, San Antonio 78284-7884.
J Clin Oncol. 1992 Apr;10(4):599-605. doi: 10.1200/JCO.1992.10.4.599.
Amplification and/or overexpression of the HER-2/neu oncogene have been shown to correlate with poor clinical outcome in patients with axillary node-positive breast cancer. In contrast, the prognostic significance of HER-2/neu in node-negative disease is controversial. This study was undertaken to evaluate further the relationship between HER-2/neu and clinical outcome in node-negative disease.
Overexpression of HER-2/neu was evaluated by permanent-section immunohistochemistry in tumors from 613 patients with long-term clinical follow-up enrolled in the Intergroup Study 0011. Patients were stratified into low-risk (n = 307) and high-risk (n = 306) groups on the basis of tumor size and estrogen-receptor (ER) status. Low-risk patients were defined as having small (less than 3 cm), ER-positive tumors and were observed without additional treatment after initial surgery. High-risk patients had either ER-negative or large (greater than or equal to 3 cm), ER-positive tumors and were randomized to be observed (n = 146) or to receive adjuvant chemotherapy (n = 160) after surgery.
The rate of HER-2/neu overexpression was 14.3% in all tumors combined and was higher in invasive carcinomas with (21.5%) than without (11.2%) a significant noninvasive or in situ histologic component (P less than .0001). There was no relationship between overexpression and clinical outcome in the natural history setting of combined low-risk and high-risk patients not receiving adjuvant therapy (n = 453). Based on the reasoning that the influence of HER-2/neu may have been obscured by high-risk features and/or the presence of noninvasive carcinoma, we also analyzed the subset of patients with low-risk lesions not containing a significant in situ component (n = 179). Patients of this group with HER-2/neu-positive tumors showed only 40% disease-free survival (DFS) at 5 years, compared with over 80% in patients with HER-2/neu-negative tumors (P less than .0001). A similar inverse correlation was observed between overexpression and overall survival in the same group of patients (P = .0001). In a separate analysis involving patients receiving adjuvant chemotherapy, those with HER-2/neu-negative tumors showed significantly improved DFS in response to therapy compared with patients with HER-2/neu-positive tumors.
Overexpression of HER-2/neu is associated with poor clinical outcome in a subset of node-negative patients with small, ER-positive, predominantly invasive tumors and may play a role in resistance to adjuvant chemotherapy.
研究表明，HER-2/neu癌基因的扩增和/或过表达与腋窝淋巴结阳性乳腺癌患者的不良临床预后相关。相比之下，HER-2/neu在淋巴结阴性疾病中的预后意义存在争议。本研究旨在进一步评估HER-2/neu与淋巴结阴性疾病临床预后之间的关系。
通过永久性切片免疫组化法评估了参与组间研究0011的613例有长期临床随访的患者肿瘤中HER-2/neu的过表达情况。根据肿瘤大小和雌激素受体（ER）状态将患者分为低风险组（n = 307）和高风险组（n = 306）。低风险患者定义为肿瘤较小（小于3 cm）、ER阳性，初始手术后无需额外治疗。高风险患者的肿瘤为ER阴性或较大（大于或等于3 cm）、ER阳性，术后随机分为观察组（n = 146）或接受辅助化疗组（n = 160）。
所有肿瘤中HER-2/neu过表达率为14.3%，有显著非浸润性或原位组织学成分的浸润性癌中HER-2/neu过表达率（21.5%）高于无此成分的浸润性癌（11.2%）（P <.0001）。在未接受辅助治疗的低风险和高风险患者合并的自然病程中，过表达与临床预后无关（n = 453）。基于HER-2/neu的影响可能被高风险特征和/或非浸润性癌的存在所掩盖这一推断，我们还分析了低风险病变且无显著原位成分的患者亚组（n = 179）。该组中HER-2/neu阳性肿瘤患者5年无病生存率（DFS）仅为40%，而HER-2/neu阴性肿瘤患者超过80%（P <.0001）。在同一组患者中，过表达与总生存率之间也观察到类似的负相关（P =.0001）。在一项涉及接受辅助化疗患者的单独分析中，与HER-2/neu阳性肿瘤患者相比，HER-2/neu阴性肿瘤患者对治疗的反应显示DFS显著改善。
HER-2/neu过表达与一部分淋巴结阴性、肿瘤较小、ER阳性、以浸润性为主的患者的不良临床预后相关，并且可能在对辅助化疗的耐药中起作用。
