Sentinel Lymph Node Occult Metastases Have Minimal Survival Effect in Node-Negative Breast Cancer Patients
Detailed examinations of sentinel lymph node tissue from breast cancer patients initially classified as negative for nodal metastases revealed occult, or previously unidentified, metastases in approximately 16 percent of the samples. Patients with these metastases had poorer overall and disease-free survival and a shorter time to distant disease diagnosis than patients without such metastases. However, the difference in 5-year survival estimates between patients with and without identified occult metastases was very small and likely not clinically meaningful. Therefore, this study did not find a clinical benefit to additional evaluation and does not justify enhancing current clinical procedures for sentinel lymph node evaluation.
The New England Journal of Medicine, February 3, 2011 (see the journal abstract).
Patients undergoing surgery to remove a breast tumor also have lymph nodes removed to determine whether cells from the tumor have metastasized and to eliminate lymph nodes containing cancer cells. In the past, most women underwent full axillary lymph node dissection (ALND), which entails the removal of at least 10 lymph nodes found in the armpit region. More recently, removal of the sentinel lymph node (the first node to which a cancer cell is likely to migrate from the primary tumor) has become standard. Sentinel lymph node biopsy (SLNB) involves the removal of just one or two nodes and is associated with less nerve damage, infections, pain, and lymphedema (swelling) than ALND.
Sentinel nodes may harbor occult metastases, which are metastases that are not detected during initial pathological examination but are identified with further evaluation. However, the clinical importance of occult metastases has not been clear. The study presented here used prospective data from a cohort of women participating in a large clinical trial of SLNB to evaluate the impact of occult metastases on outcomes.
National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32, from which this cohort was derived, was a randomized trial designed to compare outcomes in 5,611 women from the United States and Canada with operable breast cancer and clinically negative nodes who received treatment with SLNB alone or with SLNB followed by immediate ALND. (The results of this trial, which were published in Lancet Oncology in October 2010 [see the journal abstract], showed that overall survival after 8 years was similar in both groups of women.)
The authors took advantage of the availability of sentinel lymph node samples from the women in the trial to analyze the contribution of occult metastases to survival outcomes. To this end, sentinel lymph node samples from all trial participants in whom no metastases had been detected in initial analysis underwent further evaluation to identify occult metastases. A series of tissue sections from each node were evaluated by staining with hematoxylin and eosin and also by immunohistochemical staining for cytokeratins, which are breast cell surface proteins that are not normally found in lymph nodes. The protocol was designed to detect all occult metastases larger than 1.0 mm and some smaller occult metastases. When metastases were found, they were further subdivided by size into isolated tumor-cell clusters (0.2 mm or less), micrometastases (between 0.2 and 2.0 mm), and macrometastases (greater than 2.0 mm).
Outcomes (including overall survival, disease-free survival, and distant disease-free survival) were compared between patients who were found to have occult metastases and those in whom no occult metastases were detected. Statistical techniques were used to account for study group and other possible confounders.
The study was led by Dr. Donald L. Weaver of the University of Vermont Department of Pathology.
Of the 5,611 women in the trial, 3,989 were found to have negative sentinel lymph nodes on initial pathologic examination. Samples from 3,887 women were available for further analysis, and outcome information was available for all but three of these women. Occult metastases were identified in the sentinel lymph nodes of 15.9 percent of the 3,887 patients. A further breakdown by size showed that 11.1 percent of patients had isolated tumor-cell clusters, 4.4 percent had micrometastases, and 0.4 percent had macrometastases.
Patients with occult metastases had statistically significantly poorer outcomes than those without metastases, although the actual differences were small. The authors estimated that after 5 years, among patients with occult metastases, 94.6 percent were alive, 86.4 percent were free of recurrence (local, regional, or metastatic disease), and 89.7 percent had not developed metastatic disease. The corresponding estimates for patients without detectable occult metastases were 95.8 percent, 89.2 percent, and 92.5 percent, respectively. By contrast, there was no significant difference in overall patient survival based on study treatment received, SLNB alone or SLNB followed by ALND.
A subgroup analysis by size of the occult metastases provided some indication that the larger the occult metastasis, the greater the effect on patient outcome. The 5-year estimates of the proportion of patients who did not die from breast cancer were 98.4 percent for patients without detectable metastases, 97.8 percent for patients with isolated tumor-cell clusters, and 96.0 percent for patients with micro- or macrometastases. However, because of the small number of occult metastases identified overall, the authors note that confidence in these estimates is limited.
Although the results of this study support the idea that occult metastases are an independent prognostic factor, the authors note that “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.” Indeed, they note, “these minimal differences [in 5-year survival estimates between patients with and those without detectable occult metastases] do not justify changes in clinical management.”
Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis, agreed, saying, “a statistical difference is not always clinically meaningful. In this case, the differences were so small and would not be expected to have a health impact.”
However, the authors also stressed the need for continued follow-up to ensure that the survival differences remain small.