Lymph Node Ratio (LNR) as a predictive factor in addition to pNstaging in Syrian-breast cancer patients at diagnosis

 

Remal Abdulaziz Asaad

Department of Biochemistry and Microbiology, Faculty of Pharmacy, Tishreen University, Lattakia, Syria

 

ABSTRACT:

Background: Metastasis to the axillary lymph nodes is a key indicator of prognosis in breast cancer. Lymph node ratio (LNR) is reported to be superior to the absolute number of nodes involved (pN stage) in classifying patients at high versus low risk of death following breast cancer.

Aim of the study: This prospective study investigated the predictive value of the lymph node ratio (LNR) compared with the number of positive lymph nodes (pN), serum C-reactive protein (CRP) levels, hormones status and other prognostic factors in Syrian -breast cancer patients.

Patients and methods: 60 breast cancer patients aged between 32 to 77 years old, admitted in National hospital of Jableh (Lattakia-Syria) were selected from December 2015 until December 2016. LNR calculated as the ratio of the number of positive nodes to the total number of nodes excised, LNR had been categorized as low: (0 -0.2), intermediate: (>0.2 - 0.65), and high risk: (>0.65 – 1). Blood samples were collected for CRP levels on admission and measured by immunoturbidimetric determination, levels >5mg/l were considered positive. Estrogen-Receptor (ER), Progesterone Receptor (PR) and human epidermal growth factor receptor 2 (Her-2) expression were assessed.

Results: Strong relationship was found between LNR-classification system and increased number of positive lymph nodes in breast cancer patients (P< 0.0001, r = 0.91). Patients with pN>4 were at high risk (100%) in comparison with patients with pN≤4, and this difference was statistically important (P<0.0001). Results show also that strong relations were found between LNR and Grade (P=0.011), Stage (P=0.001), but not with tumor size or age (P>0.05). Mean level of CRP was 5.38 ±2.94mg/l at low LNR, 7.29±5.21mg/l at intermediate LNR and 7.68±4.55mg/l at high LNR, but the differences were not statically significant (P=0.27). Patients at high risk according to LNR-classification were positive for ER-receptor (n=4, 100%, P=0.248), PR-receptors(n=3, 75%, (P=0.028) and for Her-2 receptor (n=3, 75%, P=0.963).

Conclusion: Patients with number of positive lymph nodes more than 4 lymph nodes were at high risk according to LNR-classification system in comparison with patients with 4 lymph nodes or less as a predictive number of lymph nodes. LNR- classification was more interesting than pNstaging in comparison with level of serum CRP, but similar to other classic risk factor such as Grade, Stage, tumor size and age. LNR-classification system was interesting in positive PR-receptor expression patients as an added value of LNR for predicting future response to hormone therapy.

 

 

 

INTRODUCTION:

The breast is the leading site for cancer incidence and the second most common site for cancer death among women worldwide with an estimated 240,000 new cases among US women in 2013¹.

 

The incidence of breast cancer in Syria was 75.2 women for 100,000 according to National Center of Cancer (NCC) in 2007 and higher incidence was remarked in Tartoos and Lattakia as coastal regions. Great interest in strategies of prevention, chemoprevention, detection of early prognostic factors have been the focus of laboratory work and clinical researches for the past 30 years with increased association of breast cancer with morbidity, mortality, and enormous treatment costs².

 

Lymph node status is one of the most important prognostic factors for breast cancer. Traditionally, lymph node status is classified according to the American Joint Committee on Cancer (AJCC) as a classic breast cancer staging system based on the number of positive axillary lymph nodes where pN0 indicates zero positive nodes, pN1 1–3 positive nodes, pN2 4– 9 positive nodes and pN3≥10 positive nodes³.

 

Metastasis to the axillary lymph nodes is a key indicator of prognosis in breast cancer. The overall survival for 5-years with lymph node metastasis is 40% lower than that of patients who do not have metastasis to the lymph nodes³.

 

Many researches suggest that lymph nodes staging is not sufficient, therefore, the number of lymph nodes examined varies depending upon the surgeon’s decision, technique used, the patient’s anatomy, and the completeness of the pathological examination⁴. It is also not clear the minimal number of nodes that should be examined to establish lymph node metastasis⁵.

 

In recent years, other parameters related to the status of lymph nodes have revealed such as number of removed lymph nodes (RLNs), number of negative of lymph nodes (NLNs), and ratio of involved to removed nodes (lymph node ratio, LNR), which impact the prognosis of breast cancer patients ^6-8. Many results show that pN stage and NLN count have a better prognostic value compared to LNR in patients with breast cancer⁹.

 

Some studies have shown that no difference in prognostic value for LNR over pN¹⁰. Vinh Hung et al showed that LNR categorized as low >0 and <0.2, intermediate 0.2 to 0.65 and high risk >0.65 to 1 was better at predicting breast cancer specific mortality than pN staging¹¹. Several studies have suggested that the ratio of involved to non-involved nodes may be an alternative and possibly better indicator for disease prognosis than pN staging¹¹.

 

All these findings propose that additional studies should focus on association between number of negative lymph nodes and tumor characterizes. C-reactive protein CRP is the classical acute phase reactant protein from pentraxin family which rises in circulation in response to acute inflammation and infection. It had been reported increased levels of CRP in tissue damage, and this depending on degree of tissue damag¹². An association between CRP levels and risk of various types of cancers had been also approved, strong with lung cancer and weak with breast, prostate and colorectal cancers supporting role of chronic inflammation in carcinogenesis¹³. As a result, serum CRP levels could be a marker of increased risk for breast cancer.

 

How to select patients for safe preventive therapy is the most important question for beginning the targeted chemotherapy. In breast cancer, women at high risk (high pN staging, large tumor size, human epidermal growth factor receptor 2 (Her-2) positive, Estrogen Receptor (ER) negative, Triple Negative TN) should well studied for this prevention therapy. In fact, certain breast cancer subgroups are at high risk according to LNR categories such as women aged <35 years, Her-2 over expressing and triple negative tumors. Therefore; breast cancer prevention research needs molecularly targeted approach for success treatment and less toxic drugs¹⁴.

 

The aims of this prospective study were firstly the classification of breast cancer-patients according to LNR-classification system and to study the role of LNR in comparison with pN staging as a risk factor, and secondary to study the relation of LNR categories with other prognostic factors such as serum CRP levels, age, tumor size, histologic grade and stage.

 

MATERIAL AND METHODS:

1.    Population of Study:

Patients group:

64 Patients (male and female) had been admitted in National hospital of Jableh (Jableh-Lattakia- Syria) between December 2015 and December 2016. Basic blood investigations, chest x-ray were done for all the patients and the diagnosis was confirmed as breast cancer in sixty female and in four male. The majority of female-patients underwent a total or a subtotal mastectomy with auxiliary dissection. Data based on pathology reports which included tumor size (cm), stage, histologic grade, and t number of lymph node excised were obtained prospectively.

 

Patients excluded:

Patients with inflammation state, cardiovascular diseases and Type-2 diabetes were excluded, and also we were excluded four male-patients with breast cancer eliminating complex of differences associated with sex.

 

2.    Histological diagnosis and Breast cancer staging system:

All histologic types were diagnosed as Invasive Ductal Carcinoma IDC, Invasive Lobular Carcinoma ILC, and Mucinous carcinoma MC.

The patients were assessed according to the pathological TNM Staging according to the American Joint Committee on Cancer (AJCC) as following:

1. Tumor size: (T1 = ≤2 cm, T2 = 2.1-5 cm, T3 =>5 cm, T4 = chest wall or skin infiltration)

2. Nodal staging: (pN1 = 1-3 nodes, pN2 = 4-9 nodes, pN3= ≥ 10 nodes).

3. Metastasis: presence (M0) or absence (M1) of metastasis.

 

3.    Immunohistochemical (IHC) and Fluorescent In-Situ Hybridation (FISH) analysis:

Expression of Estrogen Receptor ER, and Progesterone Receptor PR, (positive or negative) were confirmed by Immunohistochemical analysis (IHC) and considered positive if more than 10% of tumor cells were positively (weak, moderate or strong). Expression of Her-2/neu receptor was confirmed by Fluorescent In-Situ Hybridation (FISH) analysis, and only score II or score III (intense membrane staining in more than 10% of tumor cells) were considered positive, while tumor cells with score 0 or I were negative.

 

4.    Serum CRP levels measurement:

Blood samples were collected for CRP levels on admission. CRP levels were measured by immunoturbidimetric determination using ErbaLachema Kit at 340 nm wavelength. The limit of detection is 1.5 mg/l, and the normal value of CRP being <5 mg/l. CRP levels more than 5 mg/l were considered positive for CRP measurements.

 

5.    Lymph Nodes Ratio:

Number of removed lymph nodes (RLNs), number of negative of lymph nodes (NLNs), and ratio of involved to removed nodes (lymph node ratio, LNR) were studied.

Lymph Nodes Ratio (LNR) was calculated as following: the ratio of the number of positive nodes to the total number of nodes excised, and LNR had been categorized as low: (0 -0.2), intermediate: (>0.2 - 0.65), and high risk: (>0.65 – 1).

 

6.    Statistical analysis: Descriptive statistics using frequencies (%) for categorical data were calculated. The chi-square test was used to compare percentages between groups. Two-sample Wilcoxon rank-sum (Mann-Whitney) test and Kruskal-Wallis test were used for comparing means of serum CRP levels. All analyses were completed using the Statistical Package for the Social Sciences (SPSS) version 18 (IBM Corporation).

 

As the analysis involves multiple subgroups, significance was set at the 5% level (P.value < 0.05). All analysis was done using the same method in the same laboratory and same pathologist. A written consent was signed by every patient and approved by the Institutional Ethical Board.

 

RESULTS:

1. Characteristics of patients and tumor status:

54 out of 60 patients with breast cancer were diagnosed as IDC (90%) which was the most common histologic type, 4 out of 60 patients were diagnosed as ILC (6.67%), and 2 out of 60 patients were diagnosed as Mucinous carcinoma (3.33%).

 

Female-patients were distributed by age into three groups: group (1): patients aged 40 years and younger (n=22, 36.67%), group (2): patients aged between 41 and 50 years (n=17, 28.33%), group (3): patients older than 50 years old (n=21, 35%). Mean age at diagnosis was 54.5 years (range 32 to 77 years).

 

Patients were distributed into three groups according to tumor size: T1 (n=14, 23.33%), T2 (n=37, 61.67%), and T3 (n=9, 15%). The mean size of tumors was 2.38cm with range from 1.2 to 11cm. Patients were divided according to Histologic Grade as following: Grade I: 1 patient (1.67%), Grade II: 50 patients (83.33%), Grade III: 9 patients (15%). Stage distribution was as following: stage I: 3 patients (5%), stage IIA and IIB: 28 patients (46.67%), stage IIIA and IIIB: 29 patients (48.33%). None of patients were staged as Stage IV, or with tumor size T4 as advanced tumors.

 

All characteristics of patients and tumor status are summarized in table 1.

 

Table 1: General characteristics of tumor and study population

 

2. Characteristics of patients associated with ER,PR-receptors and Her-2 receptor expressiostatus:

Concerning hormone receptor (ER and PR) and Her-2 expression, our results show that 41 patients were ER-receptor positive (68.33%), 43 patients were PR-receptor positive (71.67%), and 44 patients were Her-2 receptor positive (73.33%). The most common subtype was the triple positive TP (n=21, 35%), while only 3 patients were triple negative TN (5%) as shown in figure (1).

 

Figure 1: Characteristics of patients associated with ER,PR-receptors and Her-2 receptor expression status

 

3. Characteristics of patients and tumor associated with LNR:

Patients were devised into two groups concerning involved lymph nodes, group 1: pN ≤4 positive lymph nodes (n=23, 38.33%), and group 2: pN>4 positive lymph nodes (n=37, 61.67%).

 

Concerning LNR, patients were devised into three groups according to LNR classification as following: low: 0 to 0.2 (n=24, 40%), intermediate: >0.2 - 0.65 (n=32, 53.33%), and high risk: >0.65 – 1(n=4, 6.67%), figure (2).

Results show that the number of patients at low risk was higher in patients with pN≤4 (n=22, 91.67%) in comparison with patients with pN>4 (n=2, 8.33%). In addition, 31 patients with pN>4 were at intermediate risk (96.88%), while only one patient was at intermediate risk with pN≤4 (3.12%). Additionally, all patients with pN>4 were at high risk (n=4,100%) in comparison with patients with pN≤4, and these differences were statistically important (P<0.0001). As a result, strong relationship between pN staging and LNR (P< 0.000, r = 0.91) was remarked, see table (2).

 

Results show that strong relation was found between LNR and Stage (P=0.001). We found that number of patients increases with increased Stage as shown in table (2) and in figure (2). Concerning Stage III, our results show that (n=4, 16.67%), (n=22, 68.75%), (n=3, 75%) patients were distributed according to low, intermediate and high LNR respectively. In comparison with Stage I, there were only 2 patients at intermediate risk (6.25%) and no patient at high risk according to LNR classification, see figure (2).

 

Results show also that strong relation was found between LNR and Grade (P=0.011), for Grade III, there were 9 patients at intermediate risk, and no patient was at low or at high risk. Additionally, there was no relation statistically important found between LNR and age.

 

All these findings correlate with finding with pNstaging, data not shown.

 

 

Table 2: Characteristics of patients and tumor associated with LNR

 

Concerning relation with tumor size, LNR was not with statistically important relation with tumor size (P>0.05) although data show in table (2) that 70.83% of patients (n=17) with tumor size between (2.1-5 cm) were at low risk, while 50% of patient (n=2) with tumor size more than 5cm were at high risk according to LNR- classification. In summary, an increased high risk according to LNR-classification was found with increased Stage and with pN more than 4 lymph nodes noting the major number of patients was at low and intermediate risk as shown in figure (2) and in table (2).

Figure 2: Distribution of patients according to LNR classification, strong relation found between LNR and Stage S (P=0.001), Grade G (P=0.011) and pN satging (P<0.0001).

 

 

 

 

4. Lymph Nodes Ratio (LNR) and pN staging status associated with CRP levels:

The major pN staging group was pN2 (n=33, 55%), while 11 patients were pN0 (18.33%), and only 4 patients (6.67%) were with number of positive lymph nodes more than 10. Mean of serum CRP levels was higher in 12 patients with positive pN1 (7.75±4.24mg/l) in comparison with patients with pN0 (n=11, mean CRP =4.32 ±1.15 mg/l), and this difference was not statically important (P=0.29).

 

Our results show that mean of serum CRP levels increases with increased risk based on LNR. Mean level of CRP was 5.38 ±2.94mg/l in patients with low LNR, 7.29±5.21mg/l in patients with intermediate LNR and 7.68±4.55mg/l in patients with high LNR, patients with higher mean of CRP were at high risk (LNR >0.65-1), but the differences were not statically significant (P=0.27). Mean CRP levels associated with pN staging and LNR shown in table 3.

Table 3: Mean CRP levels associated with pN staging and LNR 

 

Figure (3) shows mean of serum CRP levels in patients according to LNR- classification system.

 

Figure 3: Distribution of patients according to mean of CRP levels and LNR classification. Mean of CRP was 5.38±2.94mg/l in patient at low risk (LNR 0 to 0.2), 7.29 ±5.21mg/l in patients at intermediate risk (LNR >0.2 - 0.65) and 7.68±4.55 mg/l in patients at high risk (LNR >0.65 – 1).

 

Figure (4) shows mean of serum CRP levels in patients according to pN staging system. Mean of CRP was 4.32±2.94 mg/l in patient with pN0, 7.75 ±4.24 mg/l in patients with pN1, 6.72±5.02 mg/l in patients with pN2 and 7±4.55 mg/l in patients with pN3.

 

Higher mean of CRP was remarked in patients with pN1 (1-3positive lymph nodes).The differences were not clear sufficient (P=0.29) in comparison with differences of CRP levels remarked with LNR.

 

Figure 4: Distribution of patients according to mean of CRP levels and pN staging. Mean of CRP was 4.32±2.94 mg/l in patient with pN0, 7.75 ±4.24 mg/l in patients with pN1, 6.72±5.02 mg/l in patients with pN2 and 7±4.55 mg/l in patients with pN3.

As a result, the major of patients were with pN2 (N=33, 55%) and at intermediate risk with LNR >0.2 - 0.65 (53.33%). Increased levels of CRP were found with increased LNR categories.

 

5. LNR- classification according to ER-receptor, PR-receptors and Her-2/neu receptor expression:

Results concerning positive ER-receptor expression show that 14 patients were at low risk (58.33%), 23 patients were at intermediate risk (71.88%) and 4 patients were at high risk (100%), and this difference was not statistically important (P=0.248). All patients with ER-negative were at low or at intermediate risk but not at high risk (n=19, 100%).

 

Results concerning positive PR-receptor expression show that 13 patients were at low risk (54.17%), 27 patients were at intermediate risk (84.38%) and 3 patients were at high risk (75%), and this difference was statistically important (P=0.028). Among 17 patients with PR-negative, there was only one patient at high risk (25%). Results concerning positive Her-2 receptor expression show that 18 patients were at low risk (75%), 23 patients were at intermediate risk (71.88%) and 3 patients were at high risk (75%), and this difference was not statistically important (P=0.963). Among 16 patients Her-2-negative, there was only one patient at high risk (25%).

 

In summary, results concerning hormone (ER, PR) receptor expression and Her-2 receptor expression show that patients positive for three hormones tested were at high risk according to LNR- classification, see table (4) and figure (5). It is important to noting that major of patients were distributed at low (n=24, 40%) and at intermediate risk (n=32, 53.33%) in comparison with number of patients at high risk (n=4, 6.67%), and at the same time, patients positive for these hormones were higher than patients negative, figure (2).

 

These finding indicate that LNR classification could be a predictive factor for expected response to future hormone therapy in patients positive for these hormones receptors.

 

Figure (4) and table (4) show hormone receptors and Her-2 receptor expression status according to LNR- classification.

 

Table 4: LNR-classification according to ER-receptor, PR-receptors and Her-2/neu receptor expression:

 

As a result, our finding show that patients at high risk according to LNR-classification (>0.65-1) were positive for ER-receptor (n=4, 100%), PR-receptor (n=3, 75%) and for Her-2 receptor (n=3, 75%), and the same results were found also at low and intermediate risk as shown in figure (5).

 

Figure 5: LNR-Classification of patients according to ER, PR receptors and Her-2 receptor expression.

 

DISCUSSION:

Lymph node status, tumor size, and histologic grade are classic pathologic and prognostic indicators in breast cancer¹⁵. Recently, pre-diagnosis factors have been identified according to increased needs for early prognostic factors. Increased levels of CRP, CRP high sensitivity (hsCRP) and interlukins within the tumor microenvironment could be considered as inflammation biomarkers in many types of cancers, and many studies have been investigated that levels of serum CRP are higher in invasive cancer than in non-invasive cancer¹⁶. More recently, many studies suggest that the number of lymph nodes retrieved and examined is highly dependent on surgical expertise, the institution’s protocol and the pathologists’ experience¹⁷. It is also not clear the total number and the minimal number of nodes that should be removed and examined to establish lymph node metastasis. Number of removed lymph nodes (RLNs), number of negative of lymph nodes (NLNs), and ratio of involved to removed nodes (lymph node ratio, LNR) should be considered in evaluation of lymph nodes status^18-20. This study aimed to classify sixty-breast cancer patients aged between 32-77 years old according to LNR-classification system and to compare them with other routine diagnostic parameters such as pNstaging, tumor size, histologic grade and stage and level of serum CRP as inflammation marker.

 

Our results show that major of patients were diagnosed as IDC (n=54, 90%), while only 4 patients were diagnosed as ILC (6.67%). In addition, the major of patients were staged as Stage II (n=28, 46.67%) and Stage III (n=29, 48.33%), Grade II (n=50, 83.33%) and with tumor size T2 (n=37, 61.67%), but no more T3 or stage IV as shown in table (1). This great homogeneity in histological diagnosis and staging could be explained by the similarity of geographic, social and ethnic situation for the population of study.

 

Concerning LNR-classification system, results suggest that strong relationship was remarked between LNR categories and Stage and Grade but not with tumor size or age. In fact, 75% of patients with stage III were at high risk (>0.65-1) and the risk according to LNR increases with increased Stage as shown in figure (1).Although statistically importance (P=0.011), increased risk (LNR) was not clear sufficient with Grade as seen in Stage because more than 83% of patients distributed as Grade II¹⁷. In addition, patients were distributed by age in wide range (32-77 years); therefore, results of age were not clear.

 

LNR-classification system was similar to pNstaging as risk factor concerning 4 positive lymph nodes exceed. In fact, all patients with pN>4 were at high risk (n=4,100%) in comparison with patients with pN≤4, this proposes an additional parameter for evaluation lymph nodes status¹⁸. As shown in figure (1), patients with pN≤4 were at low risk, while increased risk (intermediate and high) was remarked with pN>4. As a result, strong relation was remarked between risk as LNR and increased number of positive lymph nodes in patients (P< 0.0001, r = 0.91). ²⁰. Our results had been showed that pNstsging was with difference statically important with Grade (P=0.009) and with Stage (P=0.002), but not with tumor size or age, data not shown.

 

Although LNR classification was not with relation statically important with mean level of serum CRP, results show that mean level of serum CRP increases with increased risk of LNR, figure (3). Additionally, mean level of CRP was higher in patients staged as pN3 in comparison with patients with pN2 or pN0, but this difference was not clear sufficient in patients with pN1 as shown in figure (4). These findings propose that LNR classification was more interesting than pNstaging concerning level of CRP as other inflammation and prognostic factor in breast cancer.

 

For studying the value of LNR- classification according to ER-receptor, PR-receptors and Her-2/neu receptor expression, we found that the major of patients were positive for hormone receptors and for Her-2 receptor expression, and at the same time the major number of patients were also at low and intermediate risk according to LNR-classification system. Additionally, positive ER, PR- receptors and positive Her-2- receptor patients were at higher risk in comparison with patients negative for these three receptors as shown in figure (5). Concerning PR-receptor expression, our results show that 75% of positive PR-receptor was at high risk as LNR classification, which propose LNR-classification as a predictive factor for selecting patients who will benefit of hormone therapy as a predictive factor of future response for anti-PR-receptor therapy.

 

A study from Korea showed no overall difference between LNR and pN staging in categorizing poor, intermediate and good survivors, except for certain subgroup such as women aged <35 years, HER2 over expressing and triple negative tumors. Based on our results, patients positive for Her-2 at low, intermediate and high risk according to LNR were higher in comparison with patients with negative Her-2 receptor as shown in figure(5)²¹. In contrast, there was no relation between these three subgroups of patients with LNR because there were only 3 patients as TN and 4 patients <35 years ²¹.

 

The most common subtype was the Triple Positive TP (n=21, 35%), 19 patients were negative for ER-receptor expression (31.67%), while only 3 patients were TN (5%). These results support the hypothesis of homogeneity of population of current study who lived at same costal region and diagnosed as IDC (90%). As a result, these subtypes of breast cancer propose different strategies of prevention and therapy which should be well considered.

 

Overall survival (OS) or disease-free survival (DFS), death from breast cancer, and recurrence of breast cancer were not studied as a limitation of this study because of many difficulties concerning following up of patients during chemotherapy/hormone-therapy and radiotherapy. Another limitation of our study is the measurement of serum CRP level as an inflammation and prognostic factor but not specific. In fact CRP levels are easily influenced by various physiological and pathological factors like acute or chronic infections and use of anti-infectious and anti-inflammatory drugs²². In summary, our findings suggested that the use of the LNR may minimize the difference between clinical judgment and the real status of the lymph nodes that arises due to differing physician practices ²³. In fact, our results show that patients with pNstaging≥4 were at high risk according to LNR-classification system, and this correlates with results shown by San-Gang et al, in 2013 with pNstaging1-3 lymph nodes²⁴.

 

CONCLUSION:

The prevalence of breast cancer varies among countries and regions. Strong relationship was found between LNR-classification system and increased number of positive lymph nodes in breast cancer patients (P< 0.0001, r = 0.91). LNR- classification was more interesting than pNstaging in comparison with level of serum CRP, but similar to other classic risk factor such as Grade, Stage, tumor size and age. LNR-classification system was more interesting in positive PR-receptor expression patients as an added value of LNR for predicting future response to hormone therapy.

 

ACKNOWLEDGMENTS:

Thanks for Dr. Siraj Abdullah; phD in tumor surgery- National hospital of Jableh, Tishreen University, and for laboratory of pathology-Lattakia-Syria.

 

REFERENCES:

1.     Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2013. CA Cancer J Clin, 2013. 63(1): p. 11-30.

2.     Autier, P., et al., Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database. BMJ, 2010. 341.

3.     Abdulkareem, I.H., Aetio-pathogenesis of breast cancer. Nigerian Medical Journal: Journal of the Nigeria Medical Association, 2013. 54(6): p. 371-375.

4.     Vinh-Hung, V., et al., Effect of the number of uninvolved nodes on survival in early breast cancer. Oncol Rep, 2003. 20(10): p. 363–368.

5.     Danko ME., et al., Improved staging in node-positive breast cancer patients using lymph node ratio: results in 1,788 patients with long-term follow-up. J Am Coll Surg, 210 :p. 805–807

6.     Wu, S.G., et al., Prognostic value of metastatic axillary lymph node ratio for Chinese breast cancer patients. PLoS One, 2013. 8(4): p. e61410.

7.     La Torre, M., et al., Prognostic assessment of different lymph node staging methods for pancreatic cancer with R0 resection: pN staging, lymph node ratio, log odds of positive lymph nodes. Pancreatology, 2014. 14(4): p. 289-294.

8.     Arslan, N.C., et al., The prognostic impact of the log odds of positive lymph nodes in colon cancer. Colorectal Dis, 2014. 16(11): p. O386-392.

9.     Vinh-Hung, V., et al., Ratios of involved nodes in early breast cancer. Breast Cancer Research, 2004. 6(6): p. R680.

10.   Tausch C., et al., Prognostic Value of Number of Removed Lymph Nodes, Number of Involved Lymph Nodes, and Lymph Node Ratio in 7502 Breast Cancer Patients Enrolled onto Trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG). Ann Surg Oncol, 2011.19(6):p. 1808–1817.

11.   Vinh-Hung, V., et al., () Lymph node ratio as an alternative to pN staging in node-positive breast cancer. J Clin Oncol, 2009. 27(5): p.1062–1068.

12.   Erlinger, T.P., et al., C-reactive protein and the risk of incident colorectal cancer. JAMA, 2004. 291(5): p. 585-590.

13.   Guo, Y.Z., et al., Association between C-reactive protein and risk of cancer: a meta-analysis of prospective cohort studies. Asian Pac J Cancer Prev, 2013. 14(1): p. 243-248.

14.   Ahn, SH., et al., Lymph node ratio and pN staging in patients with node-positive breast cancer: a report from the Korean breast cancer society. Breast Cancer Res Treat, 2011. 139(2): p.507–515.

15.   Nakashima, J., et al., Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res, 2000. 6(7): p. 2702-2706.

16.   Wise, G.J., et al., Cytokine variations in patients with hormone treated prostate cancer. J Urol, 2000. 164(3 Pt 1): p. 722-725.

17.   Wu, S.G., et al., Prognostic value of metastatic axillary lymph node ratio for Chinese breast cancer patients. PLoS One, 2013. 8(4): p. e61410.

18.   La Torre, M., et al., Prognostic assessment of different lymph node staging methods for pancreatic cancer with R0 resection: pN staging, lymph node ratio, log odds of positive lymph nodes. Pancreatology, 2014. 14(4): p. 289-294.

19.   Arslan, N.C., et al., The prognostic impact of the log odds of positive lymph nodes in colon cancer. Colorectal Dis, 2014. 16(11): p. O386-392.

20.   Aurello, P., et al., Log odds of positive lymph nodes (LODDS): what are their role in the prognostic assessment of gastric adenocarcinoma? J Gastrointest Surg, 2014. 18(7): p. 1254-1260.

21.   Ahn SH, Kim HJ, Lee JW, Gong GY, Noh DY, et al. (2011) Lymph node ratio and pN staging in patients with node-positive breast cancer: a report from the Korean breast cancer society. Breast Cancer Res Treat 139(2): 507–515.

22.   Kim, E.S., et al., Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via C/EBPbeta and potentiates breast cancer progression. Oncogene, 2014. 33(27): p. 3583-3593.

23.   Veronesi U, Zurrida S, Viale G, Rethinking TNM, et al: A breast cancer classification to guide to treatment and facilitate research. Breast J 2009,15:291–295.

24.   San-Gang Wu1†, Yong Chen2,3†, Jia-Yuan Sun2,3†, Feng-Yan Li2,3, Qin Lin1, Huan-Xin Lin2,3 and Zhen-Yu He. Using the lymph nodal ratio to predict the risk of locoregional recurrence in lymph node-positive breast cancer patients treated with mastectomy without radiation therapy. Radiation Oncology 2013, 8:119

 

 

 

 

 

 

Received on 31.08.2017       Modified on 25.09.2017

Accepted on 24.10.2017      © RJPT All right reserved