We evaluated the prognostic significance of lymph node ratio (LNR), number of metastatic lymph nodes divided by number of removed nodes in 924 breast carcinoma patients with 1–3 metastatic axillary lymph node(s). The most significant LNR threshold value separating patients in low- and high-risk groups with significant survival difference was 0.20 for disease-free survival (
Axillary lymph node status is the most important prognostic factor in breast carcinoma and prognosis worsens with increasing number of metastatic lymph nodes [
Studies conducted in recent years indicate that the ratio of the number of metastatic lymph nodes to the number of removed lymph nodes denoted as lymph node ratio (LNR) provide a more useful prognostic information compared to nodal disease classification according to the number of metastatic lymph nodes [
In this study, we evaluated the prognostic significance of the number of removed and metastatic lymph nodes and LNR in breast carcinoma patients with 1–3 axillary metastatic lymph node(s).
We retrospectively reviewed the file records of women who underwent surgery for breast carcinoma between January 1993 and December 2001 and who were then followed up in SB Okmeydanı Training and Research Hospital. Inclusion criteria for the patients were a histological diagnosis of unilateral invasive breast carcinoma, no previous or concomitant malignant disease, known pathological tumor size (patients with T4 tumor were not included), axillary 1–3 lymph node(s) metastasis, no metastasis in ipsilateral internal mammary or supraclavicular lymph nodes and distant site at the time of diagnosis, microscopically tumor-free surgical margins, completion of adjuvant therapy planned according to standard therapy protocols, and a follow-up period of at least five years. A total of 924 patients (including 174 patients who underwent surgery at the study hospital) who met these criteria were enrolled in the current study. Clinicopathological and treatment features of the patients are shown in Table
Clinicopathological and treatment features of the patients.
Feature | Number of patients | % |
---|---|---|
Age, years | ||
Median | 48 | |
Range | 21–79 | |
<35 | 72 | 7.8 |
≥35 | 852 | 92.2 |
Menopausal status | ||
Premenopausal | 494 | 53.5 |
Postmenopausal | 430 | 46.5 |
Tumor size | ||
T1 | 281 | 30.5 |
T2 | 541 | 58.5 |
T3 | 102 | 11.0 |
Histological type | ||
Invasive ductal | 789 | 85.3 |
Invasive lobular | 67 | 7.3 |
Invasive ductal and lobular | 31 | 3.4 |
Other | 37 | 4.0 |
Surgery | ||
Modified radical mastectomy | 828 | 89.6 |
Radical mastectomy | 4 | 0.4 |
Breast-conserving | 92 | 10.0 |
Adjuvant chemotherapy | ||
Yes | 814 | 88.1 |
No | 110 | 11.9 |
Adjuvant hormonal therapy | ||
Yes | 642 | 69.5 |
No | 282 | 30.5 |
Adjuvant radiotherapy | ||
Yes | 788 | 85.3 |
No | 136 | 14.7 |
Follow-up data were obtained from file records and, in some patients, through telephone calls. The endpoint of the study was disease recurrence. Locoregional recurrence was defined as the first site of recurrence involving the chest wall (local) or/and ipsilateral axillary, supraclavicular, and internal mammary lymph nodes (regional). Locoregional recurrence concurrent with distant metastasis was recorded as locoregional recurrence. First disease recurrence was recorded as distant metastasis if it was either distant metastasis or concurrent distant metastasis and locoregional recurrence. Disease-free survival (DFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) times were defined as the time interval between tumor excision and detection of first disease recurrence, locoregional recurrence or distant metastasis respectively or the date of last follow-up. In 21 patients who developed a second malignancy (excluding basal cell carcinoma), the diagnosis date of the second malignancy was considered as the last followup date. In 9 patients whose death was unrelated to cancer, the date of death was considered as the last follow-up date. Fifty-five patients developed locoregional recurrence (including 16 patients who developed axillary recurrence), 243 patients developed distant metastasis, and 9 patients developed concomitant locoregional recurrence and distant metastasis; in patients without disease recurrence median follow-up time was 108.5 months.
The Fisher exact test was used to compare the axillary recurrence rates of the patient groups. Patients were grouped according to the number of removed and metastatic lymph nodes and LNR threshold value. Kaplan-Meier method was used for calculation and plotting of the DFS, LRFS, and DMFS curves of the patient groups, and the log-rank test was used for the comparison of the survival curves. The relative importance of the features was investigated using the Cox proportional hazards model. All comparisons were two tailed.
Survival analyses (for DFS, LRFS, and DMFS) were performed separately for the whole series and for the patient group having at least 10 lymph nodes removed from the axilla. Patients were grouped in two different ways according to the number of lymph nodes removed (grouping A: 1–5, 6–9, 10–15 and 16 and more removed lymph nodes; grouping B: 1–5 and 6 and more removed lymph nodes). To determine the LNR threshold value that will separate patients in two prognostic groups of low and high disease recurrence risk with significantly different survival rates, survival analyses were conducted with LNR threshold values between 0.10 and 0.40 for the whole series, and between 0.10 and 0.25 for the group with at least 10 lymph nodes removed, at increments of 0.05. The LNR that produced the significant survival difference between the groups and gave the highest log-rank
The median number of removed lymph nodes was 12 (range 1–38).
In grouping A, DFS was significantly worse in patients with 1–5 lymph node(s) removed compared to patients with 6–9 (
Cox proportional hazards model analysis of the clinicopathological features and the number of removed lymph nodes in terms of disease-free survival.
Feature | Relative risk | %95 CI | |
---|---|---|---|
Age, years | 0.028 | ||
<35 | 1.00 | ||
≥35 | 0.65 | 0.45–0.95 | |
Menopausal status | 0.277 | ||
Premenopausal | 1.00 | ||
Postmenopausal | 0.86 | 0.66–1.12 | |
Tumor size | <0.001 | ||
T1 | 1.00 | ||
T2 | 2.16 | 1.60–2.91 | |
T3 | 2.89 | 1.95–4.27 | |
Histological type | 0.080 | ||
Invasive ductal | 1.00 | ||
Invasive lobular | 1.07 | 0.70–1.63 | |
Invasive ductal and lobular | 1.21 | 0.68–2.12 | |
Other | 0.32 | 0.13–0.79 | |
Adjuvant chemotherapy | 0.998 | ||
Yes | 1.00 | ||
No | 1.00 | 0.66–1.50 | |
Adjuvant hormonal therapy | 0.003 | ||
Yes | 1.00 | ||
No | 1.43 | 1.12–1.83 | |
Adjuvant radiotherapy | 0.001 | ||
Yes | 1.00 | ||
No | 1.61 | 1.20–2.17 | |
Number of removed LN | 0.022 | ||
1–5 | 1.00 | ||
≥6 | 0.67 | 0.47–0.94 |
Disease-free survival rates according to the number of lymph nodes removed from the axilla. Removed lymph node(s) (RLN): 1–5 (85 patients) versus 6–9 (206 patients) (
In grouping A, LRFS was significantly worse in patients with 1–5 lymph node(s) removed compared to patients with 6–9 (
In terms of DMFS there was no significant difference between patient groups according to either grouping A or B.
Axillary recurrence was 9.4% (8/85 patients) in patients who had 1–5 lymph node(s) removed, while 0.9% (8/839 patients) in patients who had 6 or more lymph nodes removed, and the difference was significant (
The median value of LNR was 0.143 (range 0.026–1.00) for the whole series.
The most significant LNR threshold value separating patients in low- and high-risk groups in terms of DFS was 0.20 (
Disease-free survival rates according to lymph node ratio (LNR) in the whole series. LNR ≤ 0.20 (668 patients) versus LNR > 0.20 (256 patients) (log-rank
The most significant LNR threshold value separating patients in two risk groups in terms of LRFS was 0.30 (
Cox proportional hazards model analysis of the clinicopathological features and lymph node ratio in terms of locoregional recurrence-free survival in the whole series.
Feature | Relative risk | %95 CI | |
---|---|---|---|
Age, years | 0.737 | ||
<35 | 1.00 | ||
≥35 | 0.84 | 0.32–2.23 | |
Menopausal status | 0.863 | ||
Premenopausal | 1.00 | ||
Postmenopausal | 1.05 | 0.60–1.82 | |
Tumor size | 0.059 | ||
T1 | 1.00 | ||
T2 | 2.17 | 1.14–4.14 | |
T3 | 2.08 | 0.82–5.25 | |
Histological type | 0.831 | ||
Invasive ductal | 1.00 | ||
Invasive lobular | 0.95 | 0.37–2.42 | |
Invasive ductal and lobular | 0.50 | 0.07–3.70 | |
Other | 0.61 | 0.15–2.53 | |
Adjuvant chemotherapy | 0.746 | ||
Yes | 1.00 | ||
No | 0.86 | 0.36–2.05 | |
Adjuvant hormonal therapy | 0.181 | ||
Yes | 1.00 | ||
No | 1.44 | 0.84–2.47 | |
Adjuvant radiotherapy | <0.001 | ||
Yes | 1.00 | ||
No | 3.78 | 2.17–6.59 | |
Lymph node ratio | <0.001 | ||
≤0.30 | 1.00 | ||
>0.30 | 3.14 | 1.94–5.99 |
Locoregional recurrence-free survival rates according to lymph node ratio (LNR) in the whole series. LNR ≤ 0.30 (797 patients) versus LNR > 0.30 (127 patients) (log-rank
The most significant threshold value separating patients in two prognostic groups in terms of DMFS was 0.15 (
Cox proportional hazards model analysis of the clinicopathological features and lymph node ratio in terms of distant metastasis-free survival in the whole series.
Feature | Relative risk | %95 CI | |
---|---|---|---|
Age, years | 0.009 | ||
<35 | 1.00 | ||
≥35 | 0.58 | 0.39–0.87 | |
Menopausal status | 0.148 | ||
Premenopausal | 1.00 | ||
Postmenopausal | 0.80 | 0.60–1.08 | |
Tumor size | <0.001 | ||
T1 | 1.00 | ||
T2 | 2.13 | 1.53–2.97 | |
T3 | 2.94 | 1.92–4.51 | |
Histological type | 0.042 | ||
Invasive ductal | 1.00 | ||
Invasive lobular | 1.08 | 0.68–1.71 | |
Invasive ductal and lobular | 1.50 | 0.85–2.64 | |
Other | 0.24 | 0.07–0.75 | |
Adjuvant chemotherapy | 0.986 | ||
Yes | 1.00 | ||
No | 1.00 | 0.63–1.58 | |
Adjuvant hormonal therapy | 0.016 | ||
Yes | 1.00 | ||
No | 1.39 | 1.06–1.82 | |
Adjuvant radiotherapy | 0.037 | ||
Yes | 1.00 | ||
No | 1.47 | 1.02–2.12 | |
Lymph node ratio | <0.001 | ||
≤0.15 | 1.00 | ||
>0.15 | 1.72 | 1.33–2.23 |
Distant metastasis-free survival rates according to lymph node ratio (LNR) in the whole series. LNR ≤ 0.15 (501 patients) versus LNR > 0.15 (423 patients) (log-rank
As mentioned above, there was no significant relationship between the number of removed lymph nodes and survival based on any patient grouping for all three types of survival endpoint.
DFS was significantly better in patients with 1 positive node compared to those with 3 positive nodes; there was no significant difference between those with 1 and 2 positive node(s) or 2 and 3 positive nodes. Based on this, when patients were grouped as those with 1 positive node versus 2-3 positive nodes, DFS was significantly better for patients with 1 positive node (
There was no significant relationship between the number of metastatic lymph nodes and LRFS.
DMFS of patients with 1 positive node was significantly better than those with 3 positive nodes; there was no significant difference between those with 1 and 2 positive node(s) or 2 and 3 positive nodes. Based on this, when patients were grouped as those with 1 positive node versus 2-3 positive nodes, DMFS was significantly better for patients with 1 positive node (
Distant metastasis-free survival rates according to the number of metastatic lymph nodes (LN) in patients with at least 10 LN removed. 1 positive (285 patients) versus 2-3 positives (348 patients) (
The most significant LNR threshold value to separate patients in low- and high-risk groups in terms of DFS was 0.15 (
There was no significant LNR threshold value to separate patients in two prognostic groups in terms of LRFS.
The most significant LNR threshold value to separate patients in two prognostic groups in terms of DMFS was 0.15 (
Distant metastasis-free survival rates according to lymph node ratio (LNR) in patients with at least 10 lymph nodes removed. LNR ≤ 0.15 (433 patients) versus LNR > 0.15 (200 patients) (log-rank
In our series composed of patients with breast carcinoma having 1–3 metastatic axillary lymph node(s), DFS and LRFS of patients with 1–5 lymph node(s) removed from their axilla were significantly worse than those with 6 or more lymph nodes removed, and this grouping had independent prognostic significance for both types of survival outcomes. In patient groups with more than 5 lymph nodes removed, there was no significant relationship between the increased number of removed lymph nodes and DFS or LRFS. There was no significant relationship between the number of removed lymph nodes and DMFS.
Studies involving patients with 1–3 axillary lymph node metastasis indicate significantly better overall survival [
In our series, axillary recurrence rate was significantly higher in patients with 1–5 lymph node(s) removed (9.4%) compared to those with 6 or more nodes removed (0.9%). It is generally accepted that a sufficient axillary dissection to avoid leaving probable metastatic lymph nodes behind is necessary for surgical control of the disease in the axilla and for correct evaluation of the axillary status in node-positive patients. Our study results confirm this approach: high rate of axillary recurrence in patients with few lymph nodes removed indicates that actually there may be more than three metastatic lymph nodes in the axilla (N2 maybe N3 disease) and that these may have been left in the axilla.
In our study, the most significant LNR threshold value separating patients in low- and high-risk groups with significant survival difference was 0.20 for DFS, 0.30 for LRFS, and 0.15 for DMFS. All three LNR threshold values had independent prognostic significance in Cox analysis. When grouping B (with patients grouped according to 1–5 lymph node(s) removed versus 6 or more nodes removed) which had independent prognostic significance was added to these Cox analyses conducted for DFS and LRFS, its significance was lost, while the prognostic significance of LNR threshold values persisted. Since LNR is a derivative of the number of metastatic lymph nodes and the number of lymph nodes removed, it should not be included in the Cox analysis with one of these two parameters. The prognostic significance of LNR is superior to the number of lymph nodes removed for DFS and LRFS, and LNR has independent prognostic significance for DMFS while the number of removed lymph nodes has not; thus, LNR can be used to separate patients with N1 disease in low- and high-risk groups regardless of the total number of lymph nodes removed.
Series of patients having 1–3 positive lymph node(s) showed that patients with high LNR have worse survival compared to those with low LNR: Truong et al., in their series of patients having 1–39 node(s) removed and not receiving radiotherapy, determined the most significant LNR threshold value for locoregional recurrence, distant metastasis, and overall survival as 0.25, and recommended radiotherapy following mastectomy for patients with LNR > 0.25 [
In our study, different threshold values for most significant LNR for DFS, LRFS, and DMFS were identified. If the survival analyses of this study were performed for DFS only, the threshold value of 0.20 would have been higher than the most significant threshold value for DMFS (0.15) and 167 patients with LNR > 0.15–0.20 would have been classified as with low risk despite their high risk for distant metastasis. Although in daily practice, it may be difficult to determine a different threshold value for each type of disease recurrence, its potential use in planning a more appropriate adjuvant therapy should be taken into consideration.
Yildirim and Berberoglu in their series of all node-positive patients with at least 10 lymph nodes removed from the axilla, identified the optimum LNR threshold value as 0.15 for locoregional recurrence and 0.20 for distant metastasis and determined significantly higher disease recurrence rates in patients having a LNR above these thresholds [
In our study, survival analyses were conducted separately for patients with at least 10 lymph nodes removed. It is generally accepted that at least 10 lymph nodes need to be removed in order to classify nodal disease based on the number of metastatic lymph nodes according to TNM classification [
Irrespective of the number of lymph nodes removed from the axilla, LNR is a useful tool in separating breast carcinoma patients with 1–3 metastatic lymph node(s) into low- and high-risk prognostic groups. Thus, LNR may be useful to standardize adjuvant therapy for patients operated in hospitals that use different axillary dissection width and have different median number of removed lymph nodes as well as to draw reliably comparisons between treatment results coming from such different hospitals.