Attempting to identify breast cancer micrometastases and isolated tumor-cell clusters through further analysis of initially negative sentinel lymph nodes does not appear to add any clinical benefit, according to a report published online in the New England Journal of Medicine.
Researchers from the National Surgical Adjuvant Breast and Bowel Project (NSABP) determined that the presence of small occult metastases in sentinel nodes was an independent predictor of survival, but the magnitude of differences in outcome at 5 years between patients with and without occult metastases was small.
Occult metastases were detected in 15.9% of the 3,887 patients included in this analysis: 11.1% had isolated tumor-cell clusters, 4.4% had micrometastases, and 0.4% had macrometastases. There were statistically significant decreases in overall survival (P = .03), disease-free survival (P = .02), and distant-disease-free interval (P = .04) when patients with occult metastases were compared with those in whom occult metastases were not found, wrote Dr. Donald L. Weaver, professor of pathology at the University of Vermont in Burlington, and his coinvestigators.
The magnitude of differences in 5-year Kaplan-Meier estimates was just 1-3 percentage points. Comparison of patients with and without occult metastases showed rates to be 95% and 96%, respectively, for overall survival; 86% and 89%, respectively, for disease-free survival; and 90% and 93%, respectively, for distant-disease-free interval.
“Our findings argue against analysis of additional tissue levels or routine immunohistochemical analysis for sentinel-lymph-node evaluation,” Dr. Weaver and his coinvestigators wrote in the study released on Jan. 19 (doi: 10.1056/NEJMa1008108).
Increased use of serial sectioning of the sentinel lymph node (SLN) for pathologic assessment using hematoxylin and eosin (H&E) stain or immunohistochemistry has increased identification of SLNs with minimal involvement in recent years. However, the clinical significance of minimal SLN involvement – the presence of micrometastases and/or isolated tumor-cell clusters – and the optimal management of these patients have been unclear, the investigators said.
The primary aim of the phase-III NSABP trial B-32 was to evaluate equivalence of SLN biopsy alone to biopsy with complete axillary dissection. It included 5,611 women who had confirmed resectable invasive adenocarcinoma of the breast. They had to have clinically negative lymph nodes, with no positive ipsilateral axillary lymph nodes or prior removal of ipsilateral axillary lymph nodes.
In all, 2,807 women were randomized to undergo sentinel node resection immediately followed by conventional axillary dissection (arm I) and 2,804 were randomized to sentinel node biopsy with axillary lymph node dissection (ALND) only if the sentinel node was positive (arm II). SLNs from both groups were assessed postoperatively using 2-mm slices from paraffin tissue blocks and H&E staining. Routine immunohistochemistry was not permitted, but it could be done for confirmation of suspicious findings from H&E staining.
As reported at the 2010 annual meeting of the American Society for Clinical Oncology and later published (Lancet Oncology 2010;11:927-33), the investigators found no difference in disease-free or overall survival between the two groups.
This new analysis was aimed at determining the clinical significance of occult metastatic disease in selected axillary lymph nodes (sentinel nodes). It included 3,887 tissue blocks of sentinel nodes obtained from all patients with negative nodes at the initial evaluation. These were sent to a central laboratory for further evaluation. Follow-up data were available for 3,884 women. The median time in the study was 95 months.
Additional and deeper samples were evaluated for occult metastases using H&E and immunohistochemical staining. The protocol was designed “to detect virtually all occult metastases larger than 1.0 mm in the greatest dimension and to randomly detect a proportion of occult metastases smaller than 1.0 mm,” the investigators noted.
Patients were classified based on whether occult metastases were detected in the SNL. A subgroup analysis used American Joint Committee on Cancer definitions of isolated tumor-cell clusters (no larger than 0.2 mm in the greatest dimension), micrometastases (greater than 0.2 mm but no larger than 2.0 mm), and macrometastases (larger than 2.0 mm), Dr. Weaver and his coinvestigators reported.
Models were adjusted for patient age (older than 49 years or not), tumor size (no larger than 2.0 cm, 2.1 cm to 4.0 cm, or at least 4.1 cm), surgical treatment plan (lumpectomy or mastectomy), type of systemic chemotherapy, use of radiation therapy, and study group. The adjusted hazard ratios were 1.40 for death, 1.31 for any outcome event, and 1.30 for distant disease.
“Our findings are consistent with the hypothesis that nodal tumor burden is a continuous variable and indicate that occult metastases are an independent prognostic factor,” they wrote.
The differences observed between patients with and without occult metastases with respect to 5-year Kaplan-Meier estimates of overall survival (between-group difference, 1.2%), disease-free survival (2.8%), and distant-disease-free interval (2.8%) were statistically significant but relatively small, the researchers pointed out.
These findings are not surprising after a more limited presentation by NSABP investigator Thomas B. Julian at the San Antonio Breast Cancer Symposium in December. Dr. Julian reported findings only for micrometastases detected in the SLN by H&E staining alone.
The disease-free survival outcome for patients who had micrometastatic sentinel nodes by H&E stain were the same as for those who had positive sentinel nodes. “Macrometastatic patients, on the other hand, had a higher hazard rate of 1.8, which was significantly important,” Dr. Julian said.
As for overall survival, “patients who had sentinel nodes with micrometastatic disease had a hazard rate of 0.8 – very similar to those patients who were sentinel-node negative. The P value was insignificant. For those patients who had macrometastases, the hazard rate was 2.4. That was found to be significant,” said Dr. Julian, associate director of the breast care center at Allegheny General Hospital in Pittsburgh.
In the published analysis, Dr. Weaver and his associates found that occult metastases were not discriminatory predictors of cancer recurrence. Just 3.6% of the node-negative patients had regional or distant recurrences as first events, and only 30 of these events (in 0.8% of all patients) occurred in patients with occult metastases. All told, 80.5% of patients with occult metastases were alive and free of disease.
“Identification of occult metastases does not appear to be clinically useful for patients with newly diagnosed disease in whom systemic therapy can be recommended on the basis of the characteristics of the primary tumor,” the investigators wrote.
The prevalence of occult metastases was significantly associated with age younger than 50 years, clinical tumor size greater than 2.0 cm in the greatest dimension, and planned mastectomy. The authors noted that these findings are not surprising.
“Perhaps the most interesting interaction was with endocrine therapy, indicating that occult metastases are associated with estrogen receptor–positive tumors, a favorable prognostic factor, and that endocrine therapy markedly reduces the risk of a poor outcome,” Dr. Weaver and his associates wrote.
They also found that isolated tumor-cell clusters had a smaller effect on outcome than micrometastases for every outcome evaluated, regardless of whether occult macrometastases were included or excluded. The magnitude of difference in 5-year Kaplan-Meier estimates for death from breast cancer was small for detection of isolated tumor-cell clusters vs. no detection (0.6%) and for the detection of micrometastases vs. no detection (2.4%).
The B-32 trial was sponsored by the U.S. National Cancer Institute. All of the study authors reported that they have no relevant financial relationships.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
据在线发表于《新英格兰医学杂志》上的一项报告显示，对于最初前哨淋巴结(SLN)阴性的患者，做进一步分析以明确其是否存在乳腺癌微小转移和孤立性肿瘤细胞群，似乎并不能增加任何临床收益。
美国国家乳腺与肠道外科辅助治疗项目组(NSABP)的研究者们经分析判定，虽然小范围的SLN隐匿性转移是生存预后的一个独立预测因子，但有隐匿性转移者与无隐匿性转移者的5年预后差异较小。
近年来，SLN连续切片病理学评估[采用H&E染色或免疫组化试验]的使用率有所增加，从而提高了SLN微小转移的检出率。但是目前还不清楚SLN微小转移的临床意义以及对这些患者的最佳治疗。为了确定SLN隐匿性转移性的临床意义，伯灵顿佛蒙特大学病理学教授Donald L. Weaver博士及其同事进行了这项分析，并于1月19日发表了其结果(doi: 10.1056/NEJMa1008108)。
NSABP Ⅲ期临床试验的主要目的是评估单纯SLN活检与活检联合腋窝淋巴结清扫术的等效性，共纳入5,611例被确诊为可切除浸润性乳腺腺癌的女性患者。入选标准是经临床诊断为淋巴结阴性、同侧腋窝淋巴结阴性或既往无同侧腋窝淋巴结清扫术史。经过随机分组，其中2,807例立即行 SLN清扫术序贯常规腋窝淋巴结清扫术(Ⅰ组)，其余2,804例仅在SLN阳性的情况下行SLN活检联合腋窝淋巴结清扫术(ALND) (Ⅱ组)。术后将两组患者的SLN石蜡组织块切成2 mm厚的切片并采用苏木精和伊红(H&E)染色，进行比较评估。不允许常规进行免疫组化试验，但在H&E染色结果可疑时可以藉此进行验证。
对该试验的最新分析纳入了3,887例患者，其中15.9%查出有隐匿性转移：11.1%为孤立性肿瘤细胞群，4.4%为微小转移，0.4%为大体转移。有3,887个SLN组织块标本被送往中心实验室做进一步的评估，其中包含最初评估为SLN阴性的所有患者的标本。共收集了3,884例患者的随访数据，其参与研究的中位时间是95个月。根据是否存在SLN隐匿性转移性灶对患者进行分类。一项亚组分析采用了美国癌症联合委员会对孤立性肿瘤细胞群(最大径≤0.2 mm)、微小转移(最大径在0.2 mm~2.0 mm之间)和大体转移(最大径＞2.0 mm)的界定标准。根据下列因素对模型进行校正：患者年龄(＞或≤49岁)、肿瘤大小(≤2.0 cm、2.1 cm~4.0 cm或≥4.1 cm)、外科治疗计划(乳房肿块切除术或乳房切除术)、全身化疗的类型、是否使用放疗和研究分组。为了检出淋巴结最大径＞1.0 mm的几乎所有隐匿性转移灶和随机检出淋巴结最大径＜1.0 mm的部分隐匿性转移灶，研究者对从较深层组织中获取的其他标本采用H&E和免疫组化染色评估。
结果显示，与无隐匿性转移的患者相比，有隐匿性转移的患者总生存率(P=0.03)和无病生存率(P=0.02)显著降低，发生远处转移的时间显著提前(P=0.04)，结果均具有统计学意义。然而，有隐匿性转移者与无隐匿性转移者相比，5年Kaplan-Meier评估值仅相差1~3个百分点：总生存率分别为95%和96%；无病生存率分别为86%和89%；无远处转移生存率分别为90%和93%。死亡、任何终点事件以及远处转移的校正后风险比分别为1.40、1.31和1.30。就总生存率而言，SLN微小转移患者的风险比为0.8——与SLN阴性患者非常接近，无统计学意义。大体转移患者的风险比为2.4，有统计学意义。有隐匿性转移者与无隐匿性转移者之间的总生存率(组间差值为1.2%)、无病生存率(2.8%)和无远处转移间期(2.8%)的5年Kaplan-Meier评估值差异有统计学意义，但差异相对较小。
分析表明，孤立性肿瘤细胞群对每一个评估终点的影响都小于微小转移，无论是否合并隐匿性大体转移。检出孤立性肿瘤细胞群者与未检出者相比，以及检出微小转移者与未检出者相比，在因乳腺癌死亡的5年Kaplan-Meier评估值方面的差异均较小，分别为0.6%和2.4%。经H&E染色证实为SLN微小转移者的无病生存率预后与SLN阳性者相同，发生大体转移者的风险比(1.8)较大，研究者认为这有极其重要的意义。
以上结果与淋巴结肿瘤负荷是一个连续变量的假设相符，表明隐匿性转移是一个独立的预后因素，但不能有效预测癌症复发。对于新诊断的乳腺癌患者，确定是否存在隐匿性转移似乎没有临床意义，可以根据原发肿瘤的特征推荐这些患者接受全身治疗。
NSABP B-32试验接受美国国家癌症研究所的资助。本研究的所有作者均无相关的经济往来披露。
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