Small Occult Metastases in Sentinel Nodes Don't Warrant Investigation

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.

[Check out our comprehensive coverage of the San Antonio Breast Cancer Symposium.]

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 National Cancer Institute. All of the study authors reported that they have no relevant financial relationships.

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.

[Check out our comprehensive coverage of the San Antonio Breast Cancer Symposium.]

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 National Cancer Institute. All of the study authors reported that they have no relevant financial relationships.

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.

[Check out our comprehensive coverage of the San Antonio Breast Cancer Symposium.]

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 National Cancer Institute. All of the study authors reported that they have no relevant financial relationships.