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Lymph node ratio as an independent prognostic factor for breast cancer-related mortality in patients with node-positive breast cancer

1 Department of Radiation Oncology, Faculty of Medicine, Marmara University, Istanbul, Turkey
2 Anadolu Medical Center, Gebze, Kocaeli, Turkey
3 Department of Radiation Oncology, Acibadem University, Istanbul, Turkey

Date of Submission25-Nov-2019
Date of Acceptance12-Apr-2020
Date of Web Publication19-Oct-2020

Correspondence Address:
Ilknur Alsan Cetin,
Department of Radiation Oncology, Faculty of Medicine, Marmara University, Fevzi Cakmak Mah., Muhsin Yazicioglu Cd. No: 10, 34899 Pendik, Istanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1034_19

 > Abstract 

Aim: This study assessed whether prognostic information could be obtained in patients with lymph node (LN)-positive breast cancer based on their LN ratios (LNRs) and explored the relationships between other potential prognostic factors and survival.
Setting and Design: This was a retrospective clinical study.
Materials and Methods: This study included 608 women with node-positive nonmetastatic breast cancer. Clinical and pathologic data were retrospectively evaluated. The median age was 51 years (range: 23–84 years). All patients received adjuvant radiotherapy after radical surgery. A total dose of 50 Gy was administered to the chest wall or breast and LN regions with 2 Gy daily fractions. A 10-Gy boost was administered to the breast tumor bed. The cutoff value of LNR was defined as low risk (<0.21) in 278 patients, intermediate risk (0.21–0.65) in 217 patients, and high risk (>0.65) in 113 patients. Prognostic variables included patient characteristics, disease characteristics, and interventional factors. The primary endpoint was overall survival and the secondary endpoint was breast cancer-related mortality.
Statistical Analysis Used: Statistical analyses were performed using the Kaplan–Meier method, log-rank test, and Cox regression analysis. P value was required to be <0.05.
Results: Within a median follow-up period of 95.4 months (range: 5–232.4 months), overall survival rates for 10 and 15 years were 66% and 53%, respectively. Multivariate analysis revealed that LNR (P = 0.026), estrogen receptor status (ERS) (P = 0.021), age (P = 0.04), and smoking (P = 0.024) were independent significant prognostic factors for overall survival. Breast cancer-related mortality rates at 10 and 15 years were 70.7% and 60%, respectively. LNR (P = 0.03) and ERS (P = 0.002) were independent significant prognostic factors for breast cancer-related mortality.
Conclusions: LNR and ERS were significant prognostic factors for survival at all endpoints.

Keywords: Breast cancer, prognostic factors, the lymph node ratio

How to cite this URL:
Cetin IA, Akay SU, Caglar Ozkok HB, Sengoz M. Lymph node ratio as an independent prognostic factor for breast cancer-related mortality in patients with node-positive breast cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=298614

 > Introduction Top

For women, the most frequent cancer type is breast cancer and it is the primary cause of cancer-related death. Multiple randomized controlled trials and a meta-analysis have reported that adequate postoperative locoregional radiotherapy for node-positive breast cancer reduces locoregional recurrence and improves the survival rate.[1],[2] The 20-year results of the British Columbia trial also had matching results, indicating significant survival rates when radiotherapy was applied to patients with both 1–3 and 4 or more lymph node (LN) metastases.[3] In addition, a recent meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group showed that adjuvant radiotherapy after mastectomy reduced the 5-year local risk from 16% to 4% in patients with 1–3 LN metastases.[1]

LN assessment is an important disease severity and prognosis indicator in patients with breast cancer.[4],[5] It is commonly achieved through axillary LN dissection. The number of involved axillary nodes has been taken into account for routine clinical decision-making.[6],[7] LNs are classified in accordance with the American Joint Committee on Cancer LN-positive stratification (pNs) in breast cancer. The system is based on the number of positive LNs, where pN0 = no positive nodes, pN1 = 1–3 positive nodes, pN2 = 4–9 positive nodes, and pN3 = 10 or more positive nodes.[8] In several studies, the LN ratio (LNR) compared with the pNs approach is suggested to be more important for the prediction of prognosis in patients with breast cancer.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] The LNR was recently identified as a strong predictor of breast cancer survival.[12],[17],[18],[19],[20],[21],[22],[23] The LNR is calculated by dividing the number of positive LNs by the total number of excised LNs ([LN+ ]/[total LN retrieved]). Vinh-Hung et al.[16] categorized the LNR as follows: low-risk, <0.2; intermediate risk, 0.2-0.65; and high-risk, >0.65. However, other authors have reported no differences in prognostic value between the LNR and pNs approaches.[12],[14],[17],[22] Hence, the primary goal of this investigation was to determine if the LNR has the same prognostic ability as the pNs approach. In addition, we explored the long-term survival of patients receiving radiotherapy and associated prognostic factors.

 > Materials and Methods Top

In our institutional database, between 1997 and 2010, we identified 608 women with positive LNs who underwent mastectomy or breast-conserving surgery, without any detectable distant metastasis. Prognostic variables included patient characteristics (i.e., age, comorbidity, use of oral contraceptive pills, family history regarding breast cancer, smoking, pregnancy, and menopausal status), disease characteristics (i.e., tumor type, tumor laterality, location, size, grade of cell differentiation, extracapsular involvement, lymphovascular involvement, perioral involvement, number of removed LNs and positive nodes, LNR, and hormone receptor status), and interventional factors (i.e., type of surgery, safe surgical margin, chemotherapy, and hormone therapy). Patient clinicopathological characteristics are shown in [Table 1]. All patients underwent postoperative radiotherapy. A total dose of 50 Gy was administered in 25 fractions. Patients who took breast-conserving surgery or had undergone mastectomy were treated in the supraclavicular region, including the axillary apex and breast wall or breast. A total of 10 Gy radiotherapy was applied to the tumor bed with electron or photon doses during breast radiotherapy. Patients with positive hormone receptor disease received at least 5 years of adjuvant hormone therapy. Overall, 80% of the patients received hormone therapy, 46% of of the patients received tamoxifen, 31% received aromatase inhibitors, and 23% received both. In addition, 41.5% of the patients received taxane-based therapy; 40% received cyclophosphamide, epirubicin, and 5-fluorouracil therapy; and 18.5% received other chemotherapies.
Table 1: Clinicopathological characteristics of patients with breast cancer (n=608)

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The LNR was calculated as the total number of positive LNs divided by the total number of LNs obtained. The results were gathered as three groups based on established LNR cutoffs; for this study, LNR cutoffs were defined as low risk (<0.21), intermediate risk (0.21–0.65), and high risk (>0.65). The primary endpoint was overall survival and the secondary endpoint was breast cancer-related mortality. Follow-up time is the time interval between the last radiotherapy and the last follow-up or death. Overall survival is the time between the histologic diagnosis and the last contact or death. The Kaplan–Meier method was used to estimate the survival curves. The two-sided log-rank test was used to test the differences in observed survival distribution among patient subgroups. Univariate and multivariate Cox models were used to evaluate predictive factors. Hazard ratios were reported with 95% confidence intervals (CIs). All P values were two-sided and P < 0.05 was considered to indicate a significant difference. SPSS Statistics for Windows Version 20 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis.

 > Results Top

Over a 21-year period, 608 patients were diagnosed with breast cancer. The mean age at diagnosis was 51 years (range: 23–84 years). The clinicopathological characteristics of patients with node-positive breast cancer are shown in [Table 1]. A large majority of patients (88%) had 10 or more axillary LNs removed. The median number of involved LNs was 15 (range: 1–51 nodes), while the median LNR was 0.24 (range: 0.03–1.00).

The median follow-up was 7.95 years (range: 0.5–19.3 years). Overall survival rates at 5, 10, and 15 years were 80%, 66%, and 53%, respectively (95% CI: 181.1–210.6). In univariate analysis, age (<45 age, 45–65 age, and >65 age; P < 0.0001), oral contraceptive pills (P = 0.001), smoking (P = 0.01), menopausal status (P = 0.008), type of surgery (P = 0.002), tumor size (P = 0.005), number of removed LNs (1–3 LN, 4–6 LN, 6–9 LN, or ≥ 10 LN; P = 0.017), number of positive nodes (1–3 LN+, 4–9 LN+, or ≥ 10 LN+; P < 0.0001), LNR (<0.2, 0.2–0.65, >0.65; P < 0.0001), lymphovascular involvement (P = 0.007), estrogen receptor status (ERS) (P < 0.0001), progesterone receptor status (P < 0.0001), hormone therapy (P < 0.0001), and chemotherapy (P < 0.0001) were significant predictors for overall survival [Table 1]. In multivariate analysis, LNR (<0.2, 0.2-0.65, >0.65; P = 0.007), ERS (P = 0.028), age (<45 years, 45–65 years, >65 years; P = 0.02), and smoking (P = 0.03) were independent significant prognostic factors for overall survival [Table 2]. LNR was an important prognostic factor, with a 1.99-fold increased relative risk. The 10-year overall survival rates for patients with low-risk, intermediate-risk, and high-risk LNRs were 78%, 63.9%, and 37%, respectively (standard error of the mean, 7.5; 95% CI: 181–210; log-rank χ2 =59.1).
Table 2: Multivariate analysis results for overall survival

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Breast cancer-related mortality occurred in 164 (28%) patients. Breast cancer-related mortality rates at 5, 10, and 15 years were 83%, 70.7%, and 60%, respectively (95% CI: 205.1–228.3). Oral contraceptive pills (P = 0.003), pregnancy (P = 0.039), marriage (P = 0.001), tumor size (P = 0.014), type of surgery (P = 0.011), number of positive nodes (P < 0.0001), LNR (P < 0.0001), lymphovascular involvement (P = 0.016), ERS (P < 0.0001), progesterone receptor status (P < 0.0001), hormone therapy (P < 0.0001), and chemotherapy (P < 0.0001) were significant predictors for breast cancer-specific survival. LNR (<0.2, 0.2–0.65, >0.65; P = 0.008) and ERS (P = 0.004) were independent significant prognostic factors for breast cancer-related mortality [Table 3]. LNR was the most important prognostic factor, with a 1.87-fold increased relative risk. The 10-year breast cancer-specific survival rates for patients with low-risk, intermediate-risk, and high-risk LNRs were 82%, 69%, and 41.5%, respectively (standard error of the mean: 5.9; 95% CI: 205–228; log-rank χ2 =55.6) [Figure 1].
Table 3: Multivariate analysis results for breast cancer specific survival

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Figure 1: Overall and breast cancer-specific survival according to pN and according to lymph node ratio in breast cancer with positive lymph nodes

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Metastasis was detected in 164 (27%) patients; 83 (13.6%) patients had multiple metastases. In total, 13% of the patients did not experience an acute side effect during radiotherapy; Grades I, II, and III radiodermatitises were observed in 53%, 33.2%, and 0.7% of the patients, respectively. No lymphedema was observed in 85% of the patients; Grades I, II, and III lymphedemas were observed in 8%, 6.2%, and 0.8% of the patients, respectively.

 > Discussion Top

In this study, we showed that the LNR and ERS are important prognostic factors for breast cancer-related mortality. In addition, LNR, ERS, age, and smoking were independent significant prognostic factors for overall survival. The relative risk values of both LNR and ERS were higher than those of other factors.

The role of positive LNs in predicting breast cancer-related mortality and survival was recently demonstrated in several institutional series.[19],[23],[24],[25],[26] Although these studies differed in many factors (i.e., patient selection, follow-up, surgery type, and adjuvant therapies), they suggested that the percentage of positive LNs is an independent and significant survival prognostic indicator for women having LN-positive breast carcinoma. In these studies, some of the patients received radiotherapy after breast-conserving surgery while some of them didn't receive radiotherapy.[19],[23],[25],[27] In our study, all breast cancers with positive LNs were treated with locoregional radiotherapy.

Voordeckers et al. analyzed the overall survival and cause-specific survival rates as a function of the percent positive LNs in 741 patients with node-positive disease treated with breast-conserving therapy or mastectomy, 97% of whom received radiotherapy.[23] In their multivariate analysis, the percentage of positive LNs was the most significant factor associated with survival. Similar to our results, the total number of positive LNs was not statistically significant when considering the LNR. Truong et al. reported the prognostic significance of the percentage of positive axillary LNs in 542 T1–2 breast cancers with 1–3 positive LNs.[28] These findings are consistent with those of a smaller series from Megale Costa et al. involving 168 patients who had a mean follow-up of only 26 months.[24]

The LNR provided a better patient prognostic risk profile than the pNs approach. When exploring the prognostic value of LNR in our series, we used the same cutoff points identified by Vinh-Hung et al.[16] According to our retrospective multivariate analysis, LNR was statistically significant compared to pathological LNs.

Some studies have shown that percent positive axillary LN involvement predicts survival in patients with nonmetastatic postmastectomy breast cancer who are receiving regional radiotherapy.[18],[29] However, the LNR for radiotherapy treatment of 1–3 LNs may be more useful for clinical decision-making. Therefore, recent studies have focused on the LNR in patients with pN1 breast cancer.[23],[24]

In the population-based cohort study of Liu et al., LNR has been shown to be a prognostic factor, and grade-LNR staging system has been emphasized as a reliable classification.[30] Sweety et al. showed that LNR had a stronger relation with tumor grade than tumor stage.[31] If the number of removed LNs is low in breast cancer patients, there is a negative correlation between the number of removed LNs and OS (usually <10).[32] In the study of Jin et al., it was emphasized that LNR may be a strong LN staging system, especially when used in a limited number of LN dissections.[33] In the study of Wen et al., LNR is an important prognostic parameter and can predict survival more accurately than pN staging and provide an individual prediction. In addition, it is emphasized that it may help clinicians to determine treatment options and prognosis evaluation.[34]

 > Conclusions Top

In this retrospective study, two independent prognostic factors for breast cancer-related mortality were determined: the LNR was the most important, followed by the ERS.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Table 1], [Table 2], [Table 3]


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