Effect of occult metastases on survival in node-negative breast cancer

Abstract

Background: Retrospective and observational analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence or survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials according to sentinel-node involvement have been lacking.

Methods: We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Both routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension.

Results: Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant-disease-free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively.

Conclusions: Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003830.).

Figure 1. Randomization and Results of Evaluation for Occult Metastases

The patients who underwent sentinel-lymph-node (SLN) biopsy plus axillary dissection and the patients who underwent SLN biopsy alone were combined into two analytic cohorts: patients in whom occult metastases were detected and patients in whom occult metastases were not detected. The categories for metastasis size (isolated tumor-cell clusters, micrometastases, and macrometastases) were used for subgroup analysis.

Figure 2. Kaplan-Meier Survival Estimates According to the Presence or Absence of Occult Metastases Detected in Initially Negative Sentinel Lymph Nodes

Panel A shows the probability of overall survival. The Kaplan–Meier estimate of overall survival at 60 months among patients in whom occult metastases were not detected was 95.8%; among patients in whom occult metastases were detected, it was 94.6%. Panel B shows the probability of disease-free survival. The Kaplan–Meier estimate of disease-free survival at 60 months among patients in whom occult metastases were not detected was 89.2%; among patients in whom occult metastases were detected, it was 86.4%. Panel C shows the probability of distant-disease–free survival. The Kaplan–Meier estimate of distant-disease–free survival at 60 months among patients in whom occult metastases were not detected was 92.5%; among patients in whom occult metastases were detected, it was 89.7%.