Abstract
Objective
This study aimed to evaluate the association of axillary lymph node ratio (LNR) and number of positive lymph nodes (pN) with the risk of breast cancer recurrence and death.
Materials and Methods
A retrospective cohort study of node-positive stage II and III breast cancer patients diagnosed and treated between 2008 and 2009 at the Brazilian National Cancer Institute (INCA), Brazil. Overall and disease-free survival curves for number of positive lymph nodes (pN) and lymph node ratio (LNR) risk groups were constructed using the Kaplan-Meier method and compared by the log-rank test. Multivariate analysis was performed using stepwise forward Cox regression models.
Results
In total, 628 women with node-positive breast cancer were included. Most patients (69.5%) had advanced clinical stage tumors (≥IIB). The median follow-up was 58 months (range: 3–92 months). The adjusted recurrence hazard of pN2 and pN3 patients was 2.47 (95% Confidence Interval [CI] 1.72–3.56) and 2.42 (1.62–3.60), respectively, compared to pN1 patients (p<0.001), while the hazard of intermediate (0.21–0.65) and high-risk (>0.65) LNR was 2.11 (1.49–3.00) and 3.19 (2.12–4.80), respectively, compared to low-risk LNR (≤0.20) patients (p<0.001). On the other hand, the hazard of death of pN2 and pN3 patients was 2.17 (1.42–3.30) and 2.41 (1.53–3.78), respectively (p<0.001), and the hazard of intermediate (0.21–0.65) and high-risk (>0.65) LNR patients was 1.70 (1.13–2.56) and 2.74 (1.75–4.28), respectively (p≤0.001).
Conclusion
Higher pN and LNR were associated with shorter disease-free survival and overall survival times.
Keywords: Breast cancer, disease-free survival, overall survival, lymph node ratio, positive lymph nodes
Introduction
Breast cancer accounts for 23% of all cancers in women worldwide (1). The incidence is rising in developing countries, and in Brazil, 59.700 new breast cancer cases are expected in 2019 according to the Brazilian National Cancer Institute (INCA) (2).
In 1882, William Halsted introduced the radical mastectomy as the standard treatment for breast cancer and since then, axillary lymph node dissection (ALND) has been adopted as a common surgical technique for nodal assessment (3). The management of breast cancer has evolved significantly ever since and sentinel lymph node biopsy (SLNB) has been introduced into the routine clinical practice. SLNB has lower morbidity compared with classic ALND (4, 5). In a clinical trial held by The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011), clinically node-negative patients with T1–T2 tumors and patients with 1–2 positive sentinel lymph nodes (SLNs) who were treated with breast conserving-surgery and breast radiotherapy were submitted to SLNB alone or SLNB plus ALND and no differences were observed in the 10-year overall survival (OS) and disease-free survival (DFS) rates (4, 5).
Lymph node involvement has long been recognized as an important prognostic factor in breast cancer. The presence of positive axillary lymph nodes is a predictor of increased risk of local and distant recurrence, directly affecting mortality. The association between lymph node involvement and survival has been previously demonstrated (6–8) and it has been shown that overall survival rates are up to 40% lower in node-positive patients compared with node-negative ones (8).
The number of lymph nodes involved (pN) has traditionally been used for post-surgical staging of breast cancer. In addition, the lymph node ratio (LNR), defined as the ratio of positive lymph nodes to the total number of lymph nodes removed, has emerged as a prognostic factor in a growing number of studies. A higher LNR is associated with a worse prognosis in breast cancer (3, 9).
Other unfavorable prognostic factors include extracapsular invasion and perinodal fat infiltration. Several studies have shown that extracapsular extension is an important unfavorable prognostic factor in many types of cancer, including breast cancer (1, 6, 7, 10, 11). The relevance of extracapsular invasion and perinodal fat infiltration as a risk factor for local and distant recurrence in women with breast cancer has been demonstrated by several studies (1, 11). In addition, some studies have suggested an association between other indicators of the extent of axillary disease such as the size of nodal metastasis and prognosis (7, 12, 13).
This study aimed to evaluate the effect of pN and LNR on overall survival and disease-free survival of women with node-positive breast cancer.
Material and Methods
This is a retrospective cohort study of node-positive breast cancer patients (ICD-10, C50) diagnosed and treated between 2008 and 2009 in a reference cancer center in Brazil. The study was approved by the INCA Research Ethics Committee under protocol number 128/11.
Patients 18 years of age and older presenting with clinical stage II and III breast cancer were included. As per institutional routine, all patients underwent mastectomy or segmental resection + ALND (Berg levels I, II or I, II and III) with or without previous axillary lymph node biopsy.
Patients without information on clinical stage (two patients) and number of positive lymph nodes (four patients) were excluded.
Patients were identified from the Hospital Cancer Registry (RHC). Data were collected directly from physical and electronic hospital records and medical charts. The following sociodemographic variables were evaluated: age (<50 years or ≥50 years), ethnicity (Caucasian or others), education (<8 years or ≥8 years of education), and marital status (with or without partner). The tumor variables evaluated were: clinical stage (<IIB or ≥IIB), histological type (non-special type invasive carcinoma or others), Elston histological grade (1–2: low grade; 3: high grade), estrogen and progesterone receptor status (positive or negative), and Her-2 overexpression (positive or negative).
These axillary specimens were carefully examined by pathologists with a large experience in breast cancer. The pathology process was standardized by the use of a combination of entire submission, fat clearing, visualization and palpation, in order to increase the detection of lymph nodes. Axillary lymph nodes were examined for the total number of lymph nodes removed, number of positive lymph nodes (pN), and lymph node ratio (LNR.) The number of positive lymph nodes on histopathological examination was stratified according to the staging system of the American Joint Committee on Cancer and The Union for International Cancer Control (AJCC/UICC) into pN1 (1–3 positive lymph nodes), pN2 (4–9 positive lymph nodes), and pN3 (≥10 positive lymph nodes) (14, 15). Patients were grouped into low- (LNR≤0.20), intermediate- (LNR 0.21–0.65), and high-risk (LNR>0.65) LNR groups based on the staging classification proposed by Vinh-Hung et al. (10). In addition, perinodal fat invasion and/or extracapsular invasion (yes/no) were also evaluated.
Surgical treatment consisted of mastectomy or segmental resection + ALND. Data on the following adjuvant treatments were also evaluated: radiotherapy in the residual breast tissue or chest wall (yes/no), chemotherapy (yes/no), hormone therapy (yes/no), and trastuzumab (yes/no).
Survivor patients were followed-up at least 5 years. Disease-free survival (DFS) and overall survival (OS) were endpoints of the study. Locoregional recurrence was defined as a pathologically proven recurrence in the ipsilateral chest wall, supraclavicular and infraclavicular regions, axilla, and internal mammary area. Distant metastasis was defined as recurrence at any site other than those above described and was confirmed by imaging studies and histopathological evidence when necessary. DFS was defined as the time from the date of surgery until local or distant relapse was detected (event) or the last follow-up date. OS was defined as the interval between initial diagnosis and death (event) or the last follow-up date.
Descriptive statistics were used for the calculation of measures of central tendency and dispersion for continuous variables and frequency distributions for categorical variables. Differences in median were compared by Mann–Whitney test. Overall and disease-free survival curves for different pN and LNR risk groups were constructed using the Kaplan-Meier method and compared by the log-rank test at p<0.05. Multivariate analysis was performed using stepwise forward Cox regression models, and all variables associated with the outcome variables at p<0.20 on univariate analysis were included in multivariate models. A p value <0.05 was considered statistically significant in the final model. All analyses were performed using Statistical Package for the Social Sciences version 21.0.0 (IBM Corp,.; Armonk, NY, USA).
Results
During the study period, 628 women underwent surgery for invasive breast cancer with axillary lymph node involvement and no distant disease. The median age was 54 years (range: 23–91 years), most women were Caucasian (55%), single (54%), and had completed eight or more years of education (57%) (Table 1).
Table 1.
Clinicopathologic characteristics of patients with node-positive breast cancer (n=628)
| Variables | N | % |
|---|---|---|
| Age at diagnosis ≥50 years | 408 | 65.0 |
| Median (min-max) | 54 (23–91) | |
| Schooling ≥8years | 360 | 57.3 |
| Race/ethnicity White | 348 | 55.4 |
| Marital Status Living without a partner | 337 | 53.7 |
| Clinical Staging | ||
| I | 42 | 6.7 |
| IIA | 150 | 23.9 |
| IIB | 148 | 23.6 |
| IIIA | 86 | 13.7 |
| IIIB | 192 | 30.6 |
| IIIC | 10 | 1.6 |
| Histological type | ||
| Non-special type invasive carcinoma | 549 | 87.4 |
| Lobular infiltrating carcinoma | 36 | 5.7 |
| Other | 43 | 6.8 |
| Histological grade | ||
| Grade 1 | 38 | 6.1 |
| Grade 2 | 193 | 30.7 |
| Grade 3 | 300 | 47.8 |
| Estrogen receptor Positive | 480 | 76.4 |
| Progesterone receptor Positive | 413 | 65.8 |
| Her-2 Positive | 148 | 23.6 |
| Surgery Mastectomy | 572 | 91.1 |
| Trastuzumab Neo and/or adjuvant | 106 | 16.9 |
| Chemotherapy Neo and/or adjuvant | 524 | 83.4 |
| Radiotherapy Neo or adjuvant | 361 | 57.5 |
| Hormone therapy Neo and/or adjuvant | 417 | 66.4 |
| Tumor infiltration fat/perinodal extravasation | 222 | 35.4 |
| Number of lymph nodes removed 10 | 616 | 98.1 |
| Median (min-max) | 19 (6–77) | |
| Number of positive lymph nodes | ||
| Median (min-max) | 4 (1–49) | |
| pN1 (1–3) | 304 | 48.4 |
| pN2 (4–9) | 186 | 29.6 |
| pN3 (≥10) | 138 | 22.0 |
| Lymph node ratio | ||
| Median (min-max) | 0.20 (0.02–1.00) | |
| Low risk (≤0.20) | 318 | 50.6 |
| Intermediate risk (0.20–0.65) | 208 | 33.1 |
| High risk (>0.65) | 102 | 16.2 |
Missing values: Schooling (5; 0.8%); Marital Status (1; 0.2%); Histological grade (97; 1.4%)
pN: Number of positive lymph nodes
Most patients had advanced clinical stage tumors (≥IIB); the predominant histological subtype was high-grade (48%) invasive carcinoma of no special type (87%). Estrogen and progesterone receptors were positive in 76% and 66% of cases, respectively, and Her-2 overexpression was observed in 24% of patients (Table 1).
The median number of lymph nodes removed per patient was 19 (range: 6–77; median=18 in the neoadjuvant chemotherapy group; 20 in the adjuvant chemotherapy group; and 19 in the no chemotherapy group; p=0.998). Nearly all women (98%) had 10 or more lymph nodes removed, and the median number of positive lymph nodes was four (range: 1–77). Based on the AJCC/UICC staging system, 304 patients were classified as pN1 (48%), 186 (30%) as pN2, and 138 (22%) as pN3 according to the number of positive lymph nodes (Table 1).
Fifty-one percent of patients had lymph node ratio (LNR)<0.20 (low-risk), 33% had LNR of 0.21–0.65 (intermediate-risk), and 16% of patients had LNR>0.65 (high-risk). Extracapsular invasion and/or perinodal fat infiltration were observed in 35% of patients.
Mastectomy was the treatment of choice in 91% of cases. Chemotherapy was administered in 83.4% of patients (neoadjuvant=263 patients [41.9%]; adjuvant=309 patients [49.2%]; both=48 patients [7.6%]) 66.4% received hormone therapy, and 17% of patients were treated with Trastuzumab (neoadjuvant=10 patients [1.6%]; adjuvant=351 patients [55.9%]) (Table 1). Neoadjuvant radiotherapy was performed in locally advanced tumors that did not respond to neoadjuvant chemotherapy and were inoperable before neoadjuvant radiotherapy.
The median follow-up was 58 months (range: 3–92 months). Disease-free survival times of pN1, pN2, and pN3 patients were 53.8, 45.9, and 43.5 months, respectively (p<0.001). Overall survival times of pN1, pN2, and pN3 patients were 56.0, 52.3, and 50.0 months, respectively (p<0.001) (Table 2, Figure 1a, c).
Table 2.
Five-year disease-free survival and overall survival according to the number of positive lymph nodes and lymph node ratio
| Variables | 5-year disease free survival | |
|---|---|---|
| % (SD) | p | |
| Number of positive lymph nodes | <0.001 | |
| pN1 (1–3) | 80.1 (2.4) | |
| pN2 (4–9) | 53.9 (3.8) | |
| pN3 (≥10) | 50.6 (4.4) | |
| Total | 65.8 (2.0) | |
| Lymph node ratio | <0.001 | |
| Low risk (≤0.20) | 79.2 (2.4) | |
| Intermediate risk (0.20–0.65) | 55.9 (3.5) | |
| High risk (>0.65) | 45.4 (5.1) | |
| Total | 65.9 (2.0) | |
| Variables | 5-year overall survival | |
| % (SD) | p | |
|
| ||
| Number of positive lymph nodes | <0.001 | |
| pN1 (1–3) | 84.3 (2.2) | |
| pN2 (4–9) | 69.4 (3.5) | |
| pN3 (≥10) | 62.3 (4.3) | |
| Total | 75.1 (1.8) | |
| Lymph node ratio | <0.001 | |
| Low risk (≤0.20) | 83.4 (2.2) | |
| Intermediate risk (0.20–0.65) | 70.8 (3.3) | |
| High risk (>0.65) | 57.4 (5.1) | |
| Total | 75.1 (1.8) | |
Figure 1. a–d.
Kaplan-Meier Overall Survival estimates according to the number of positive lymph nodes (pN) and lymph node ratio (LNR) (a, b). Kaplan-Meier Disease Free Survival estimates according to the number of positive lymph nodes (pN) and lymph node ratio (LNR) (c, d)
The median disease-free survival times of low-, intermediate-, and high-risk LNR patients were 53.6, 46.3, and 41.5 months, respectively (p<0.001). In addition, the median overall survival times of low-, intermediate-, and high-risk LNR patients were 55.6, 52.9, and 48.8 months, respectively (p<0.001) (Table 2, Figure 1b, d).
The univariate analysis of sociodemographic and clinical variables with risk of local recurrence and risk of death is presented in Table 3 and 4, respectively. The univariate and multiple Cox regression models for disease-free survival and overall survival are presented in Table 5.
Table 3.
Five-year disease-free survival and univariate analysis for the risk of recurrence in node-positive breast cancer
| Variables | 5-Year DFS % (SD) | Hazard Ratio (95% CI) | p |
|---|---|---|---|
| Age at diagnosis | |||
| <50 years | 61.5 (3.3) | Reference | 0.106 |
| ≥50 years | 68.5 (2.4) | 1.26 (0.95–1.67) | |
| Schooling | |||
| <8 years | 62.4 (3.1) | 1.27 (0.96–1.67 | 0.094 |
| ≥8 years | 68.4 (2.5) | Reference | |
| Race/ethnicity | |||
| White | 68.7 (2.6) | 0.81 (0.61–1.07) | 0.132 |
| Others | 62.5 (3.0) | Reference | |
| Marital Status | |||
| Living without a partner | 66.1 (2.7) | 0.97 (0.74–1.28) | 0.843 |
| Living with a partner | 65.7 (2.8) | Reference | |
| Clinical Staging | |||
| ≥II B | 58.4 (2.4) | 2.85 (1.95–4.18) | <0.001 |
| <II B | 83.0 (2.8) | Reference | |
| Histological type | |||
| Non-special type invasive carcinoma | 64.5 (2.1) | 1.68 (1.03–2.72) | 0.037 |
| Others | 75.7 (5.0) | Reference | |
| Histologic grade | |||
| Low | 77.5 (2.8) | Reference | <0.001 |
| High | 56.1 (3.0) | 2.33 (1.67–3.23) | |
| Estrogen receptor | |||
| Negative | 48.7 (4.3) | 2.22 (1.66–2.97) | <0.001 |
| Positive | 71.1 (2.1) | Reference | |
| Progesterone receptor | |||
| Negative | 53.6 (3.5) | 2.01 (1.52–2.65) | <0.001 |
| Positive | 72.3 (2.3) | Reference | |
| Her-2 | |||
| Negative | 69.0 (2.2) | Reference | 0.003 |
| Positive | 56.6 (4.1) | 1.56 (1.16–2.10) | |
| Surgery | |||
| Mastectomy | 63.9 (2.1) | 3.20 (1.50–6.80) | 0.003 |
| Conservative | 86.8 (4.6) | Reference | |
| Trastuzumab | |||
| Yes | 61.2 (4.7) | 1.26 (0.89–1.77) | 0.192 |
| No | 66.9 (2.1) | Reference | |
| Chemotherapy | |||
| Yes | 64.1 (2.1) | 1.64 (1.06–2.56) | 0.028 |
| No | 76.3 (4.6) | Reference | |
| Radiotherapy | |||
| Yes | 67.1 (2.5) | 0.87 (0.66–1.15) | 0.319 |
| No | 64.3 (3.1) | Reference | |
| Hormone therapy | |||
| Yes | 74.0 (2.2) | 0.39 (0.30–0.52) | <0.001 |
| No | 48.9 (3.7) | Reference | |
| Tumor infiltration fat/perinodal extravasation | |||
| Yes | 63.0 (3.3) | 1.21 (0.92–1.61) | 0.180 |
| No | 67.5 (2.4) | Reference | |
| Number of Lymph nodes removed | |||
| <10 | 72.7 (13.4) | Reference | |
| ≥10 | 65.8 (2.0) | 1.46 (0.47–4.57) | 0.516 |
DFS: Disease Free Survival; SD: standard deviation; CI: confidence Interval
Table 4.
Five-year overall survival and univariate analysis for the risk of death in node-positive breast cancer
| Variables | 5-Year OS % (SD) | Hazard Ratio (95% CI) | P |
|---|---|---|---|
| Age at diagnosis | |||
| <50 years | 75.3 (3.0) | 0.950 (0.68–1.33) | 0.763 |
| ≥50 years | 75.0 (2.2) | Reference | |
| Schooling | |||
| <8 years | 72.7 (2.9) | 1.15 (0.83–1.59) | 0.391 |
| ≥8 years | 76.7 (2.3) | Reference | |
| Race/ethnicity | |||
| White | 77.9 (2.3) | 0.75 (0.54–1.03) | 0.079 |
| Others | 71.7 (2.8) | Reference | |
| Marital Status | |||
| Living without a partner | 74.4 (2.5) | 1.13 (0.81–1.56) | 0.470 |
| Living with a partner | 76.1 (2.6) | Reference | |
| Clinical Staging | |||
| ≥II B | 68.4 (2.3) | 3.41 (2.10–5.52) | <0.001 |
| <II B | 90,1 (2.2) | Reference | |
| Histological type | |||
| Non-special type invasive carcinoma | 73.9 (1.9) | 1.80 (1.00–3.26) | 0.049 |
| Others | 83.5 (4.4) | Reference | |
| Histologic grade | |||
| Low | 87.7 (2.2) | Reference | <0.001 |
| High | 63.2 (2.9) | 3.32 (2.19–5.01) | |
| Estrogen receptor | |||
| Negative | 55.4 (4.4) | 3.01 (2.17–4.19) | <0.001 |
| Positive | 80.7 (1.8) | Reference | |
| Progesterone receptor | |||
| Negative | 63.9 (3.4) | 2.20 (1.60–3.04) | <0.001 |
| Positive | 80.6 (2.0) | Reference | |
| Her-2 | |||
| Negative | 77.7 (2.0) | Reference | 0.006 |
| Positive | 66.6 (4.0) | 1.62 (1.15–2.28) | |
| Surgery | |||
| Mastectomy | 73.4 (1.9) | 4.10 (1.52–11.09) | 0.005 |
| Conservative | 92.3 (3.7) | Reference | |
| Trastuzumab | |||
| Yes | 71.6 (4.5) | 1.18 (0.79–1.78) | 0.409 |
| No | 75.8 (1.9) | Reference | |
| Chemotherapy | |||
| Yes | 73.3 (2.0) | 1.78 (1.02–3.09) | 0.040 |
| No | 85.4 (3.8) | Reference | |
| Radiotherapy | |||
| Yes | 78.1 (2.2)) | 0.68 (0.49–0.94) | |
| No | 70.8 (2.9) | Reference | 0.020 |
| Hormone therapy | |||
| Yes | 84.4 (1.8) | 0.27 (0.19–0.37) | |
| No | 55.5 (3.6) | Reference | <0.001 |
| Tumor infiltration fat/perinodal extravasation | |||
| Yes | 70.6 (3.1) | 1.34 (0.97–1.86) | 0.074 |
| No | 77.6 (2.1) | Reference | |
| Number of Lymph nodes removed | |||
| <10 | 90.9 (8.7) | Reference | 0.542 |
| ≥10 | 74.8 (1.8) | 1.54 (0.38–6.23) | |
OS: overall survival; SD: standard deviation; CI: confidence interval
Table 5.
Cox regression model (crude and adjusted) for risk of recurrence and death
| Variables | N (%) | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|---|
|
| ||||||
| Yes | No | HR (95% CI) | p | HR (95% CI) | p | |
| Risk of Recurrence | ||||||
| Number of lymph nodes positive* | ||||||
| pN1 (1–3) | 57 (28.1) | 247 (58.3) | Reference | Reference | ||
| pN2 (4–9) | 82 (40.4) | 103 (24.3) | 2.70 (1.93–3.79) | <0.001 | 2.47 (1.72–3.56) | <0.001 |
| pN3 (≥10) | 64 (31.5) | 74 (17.5) | 3.09 (2.16–4.42) | <0.001 | 2.42 (1.62–3.60) | <0.001 |
| Lymph node ratio** | ||||||
| Low risk (≤0.20) | 63 (31.0) | 255 (60.1) | Reference | Reference | ||
| Intermediate risk (0.20 – 0.65) | 88 (43.3) | 120 (28.3) | 2.41 (1.74–3.32) | <0.001 | 2.11 (1.49–3.00) | <0.001 |
| High risk (>0.65) | 52 (25.6) | 49 (11.6) | 3.38 (2.34–4.88) | <0.001 | 3.19 (2.12–4.80) | <0.001 |
| Risk of Death | ||||||
| Number of lymph nodes positive*** | ||||||
| pN1 (1–3) | 46 (30.9) | 258 (53.9) | Reference | Reference | ||
| pN2 (4–9) | 55 (36.9) | 131 (27.3) | 2.10 (1.42–3.12) | <0.001 | 2.17 (1.42–3.30) | <0.001 |
| pN3 (≥10) | 48 (32.2) | 90 (18.8) | 2.71 (1.81–4.07) | <0.001 | 2.41 (1.53–3.78) | <0.001 |
| Lymph node ratio**** | ||||||
| Low risk (≤0.20) | 51 (34.2) | 267 (55.7) | Reference | Reference | ||
| Intermediate risk (0.20 – 0.65) | 58 (38.9) | 150 (31.3) | 1.85 (1.27–2.69) | 0.001 | 1.70 (1.13–2.56) | 0.011 |
| High risk (>0.65) | 40 (26.8) | 62 (12.9) | 2.97 (1.96–4.49) | <0.001 | 2.74 (1.75–4.28) | <0.001 |
Adjusted for clinical stage, hormone therapy, histological grade, and age
Adjusted for clinical stage, hormone therapy, histological grade, histological type, and age
Adjusted for clinical stage, histological grade, hormone therapy, and radiotherapy
Adjusted for clinical stage, histological grade, hormone therapy, and radiotherapy
In the DFS model, the adjusted five-year risk of breast cancer recurrence of pN2 and pN3 patients was 2.47 and 2.42 times greater, respectively, than that of pN1 patients (p<0.001). In addition, the five-year recurrence risk of intermediate- and high-risk LNR patients was 2.11 and 3.19 times greater, respectively, than that of low-risk LNR patients (p<0.001) (Table 5).
In the OS model, the adjusted risk of death was greater in pN2 (HR=2.17, 95% CI: 1.42–3.30) and pN3 (HR=2.41, 95% CI: 1.53–3.78) patients than in pN1 patients. In addition, the risk of death of intermediate- and high-risk LNR patients was 1.70 (p=0.011) and 2.74 (p<0.001) times greater, respectively, than that of low-risk LNR patients (Table 5).
Discussion and Conclusion
This study evaluated a large cohort of women with breast cancer who were treated at a single oncology center. The results showed that the number of lymph nodes involved and lymph node ratio were useful predictors of risk of recurrence and risk of death in women with breast cancer.
Lymph node status has been widely regarded as an important prognostic factor in breast cancer and the TNM classification system remains the gold standard for staging the disease (3, 8, 9, 14, 15). Axillary lymph node status has been used for prognostic assessment and for guiding adjuvant, local or systemic treatment decisions (10, 16–20).
Some studies have shown that LNR improves the prognostication system compared with the use of pN alone (9). The importance of LNR has been demonstrated in colon, esophageal, gastric, pancreatic, bladder, vulvar, and cervical cancer (9), and there is now growing evidence of its prognostic value in breast cancer (3, 21, 22).
Vinh-Hung et al. (9) investigated 1.829 women diagnosed with node-positive breast cancer between 1980 and 2004 and identified LNR cutoff points that more accurately predicted the risk of breast cancer death and specific-survival rates, especially after 10 years. The authors showed that LNR predicts survival after breast cancer more accurately than the pN classification of the TNM staging system and suggested that LNR should be considered as an alternative or improvement to pN staging. In that study, the breast cancer-specific survival rates at 10 years for patients with LNR ≤0.20, LNR=0.21–0.65, and LNR >0.65 were 75%, 63%, and 40%, respectively. In addition, the adjusted hazard ratio of breast cancer mortality risk was 1.78 (95% CI: 1.46–2.18) for patients in the intermediate LNR risk group (LNR=0.21–0.65) and 3.21 (95% CI: 2.54–4.06) for patients in the high LNR (>0.65) risk group compared with patients in the low LNR risk group. Similarly, Kim et al. (22) analyzed 3.477 patients with T1–T2 node-positive breast cancer and demonstrated the clinical relevance of LNR, which was characterized by cutoff points similar to those reported by Vinh-Hung et al. (9). In addition, using another cut-off, Kuru et al. (23) found that P/N ratio >0.25 was associated with a high risk of death (HR 3.8, CI 2.74–5.50).
More recently, following the results of randomized clinical trials such as the International Breast Cancer Study Group 23-01 (IBCSG 23-01) (24) and ACOSOG Z0011 (4, 5), the role of LNR has been called into question. Nevertheless, even in patients that do not meet the criteria used in these two studies (patients with early disease and, in general, who receive adjuvant treatment such as local radiotherapy), LNR has superior prognostic value compared with pN. Thus, the role of LNR remains unquestionable in advanced cases of breast cancer (9, 15, 25).
Contrary to other studies (1, 7, 11, 22), there were no significant differences in disease-free survival (HR=1.21, 95% CI: 0.92–1.61; p=0.180) and overall survival (HR=1.34, 95% CI: 0.97–1.86; p=0.074) between patients with and without extracapsular invasion and perinodal fat infiltration.
Some limitations of the current study should be highlighted. The data analyzed here are from a pre-ACOSOG Z0011 cohort series of patients who were diagnosed and treated between 2008 and 2009, when patients with positive lymph nodes on SLNB were treated with axillary dissection. In addition, all cases were collected from a single cancer center, which may adversely affect external validity because cases may not be representative of the general population. Nevertheless, some strengths of the study should be noted. This is a single-center study and the same diagnostic and treatment procedures were used for all patients during the study period, strengthening the internal validity of the data. The histopathological data were examined by a team of experienced pathologists specialized in breast cancer, improving the reliability of results. In addition, histopathological variables were extracted directly from electronic charts minimizing information bias. Another strength of the study is the relatively short inclusion period (two years), which prevented novel technologies and changes in treatment choice from affecting prognosis. Lastly, the long follow-up time enabled the accurate identification of the outcomes analyzed.
The era of personalized molecular medicine and genomics-based tumor profiling is paving the way to precision medicine (26, 27). However, this high-cost approach to disease treatment and prevention is far from the reality of most patients in developing countries like Brazil, especially those relying on public health services. Nowadays, Oncotype DX testing and biomarkers (Her-2, RE, RP) are important players in clinical decision-making. They are expensive; hence, some poor countries may have uncertainties in making them available for systematic clinical use. In this context, data such as pN and LNR are important and low-cost prognostic factors. Thus, we believe that extracting additional useful information from histopathological reports at no extra costs, such as lymph node ratio, may benefit a significant number of patients and therefore should be implemented as prognostic factors of node-positive breast cancer.
In women with node-positive breast cancer, the number of positive lymph nodes (pN) and lymph node ratio (LNR) are important prognostic factors of disease-free survival and overall survival.
Footnotes
Ethics Committee Approval: Ethics committee approval was received for this study from the Ethics Committee of Instituto Nacional de Câncer (128/11).
Informed Consent: Informed consent was not taken due to retrospective design of the study.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept - F.T., L.C.S.T.; Design - F.T., A.B.; Supervision - L.C.S.T., A.B.; Data Collection and/or Processing - F.T., K.A., S.S.A.; Analysis and/or Interpretation - F.T., L.C.S.T., A.B., M.A.B.; Literature Search - F.T., M.A.B.; Writing Manuscript - F.T., L.C.S.T., A.B.; Critical Review - L.C.S.T., A.B.
Conflict of Interest: The authors have no conflicts of interest to declare.
Financial Disclosure: The authors declared that this study has received no financial support.
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